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WO2024041654A1 - 含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂 - Google Patents

含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂 Download PDF

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WO2024041654A1
WO2024041654A1 PCT/CN2023/115117 CN2023115117W WO2024041654A1 WO 2024041654 A1 WO2024041654 A1 WO 2024041654A1 CN 2023115117 W CN2023115117 W CN 2023115117W WO 2024041654 A1 WO2024041654 A1 WO 2024041654A1
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group
formula
substituted
halogen
combination
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French (fr)
Inventor
杨光富
周立明
成传祥
陈梦迪
李鸿浩
柴松
张璞
熊姿
吴耀军
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JIANGSU FLAG CHEMICAL INDUSTRY Co Ltd
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JIANGSU FLAG CHEMICAL INDUSTRY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides

Definitions

  • the invention relates to the field of pesticides and fungicides, and specifically to compounds containing chain carboxylic acid amide structures, their preparation methods and applications, and fungicides.
  • Oomycetes are one of the important pathogenic bacteria that cause plant diseases. They have the characteristics of wide parasitic range, strong destructiveness, high harm, and rapid development.
  • Downy mildew is one of the most representative oomycetes. It has a short incubation period and can be infected multiple times. It can cause a disease pandemic in a very short period of time. For example, cucumber downy mildew caused by this pathogen can spread in just a few days. All cucumbers died.
  • plant diseases caused by downy mildew can be divided into the following three categories: 1) Leaf diseases, mainly downy mildew; 2) Root and crown diseases of annual and perennial crops, such as wet soil, seedling wilting, root, neck and stem rot Disease; 3) Systemic diseases refer to diseases caused by root infection of soil or seeds, the distribution of pathogens in the vascular system of plants, and the manifestation of symptoms on growing points or leaves.
  • the purpose of the present invention is to overcome the aforementioned shortcomings of the prior art and provide a new type of oomycete fungicide that has no cross-resistance with traditional fungicides.
  • the first aspect of the present invention provides a compound containing a chain carboxylic acid amide structure or an agrochemically acceptable salt, hydrate and solvate thereof, the compound having a structure represented by formula (I) ,
  • one of X 1 and X 2 is S, and the other is CH;
  • R is the structure shown in formula (Q1) or the structure shown in formula (Q2);
  • R 1 , R 2 and R 3 are each independently selected from H, C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group, C 3 -C 12 cycloalkyl group , C 1 -C 12 alkylthio group, C 1 -C 12 alkoxy group substituted by at least one halogen, C 1 -C 12 alkoxy group substituted by phenyl, halogen, phenyl, composed of combination A middle phenyl, cyano, nitro, pyridyl, pyrazolyl substituted by at least one group in combination A; or, R 2 and R 3 are cyclized together Forming a 3-7 membered saturated heterocyclyl group containing at least one O atom as a ring atom that is unsubstituted or substituted by at least one group in the combination A; A is N or CH; and when A is N, R 2 and one of R 3 does not exist;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group, C 3 -C 12 Cycloalkyl, C 1 -C 12 alkylthio group, C 1 -C 12 alkoxy group substituted by at least one halogen, C 1 -C 12 alkoxy group substituted by phenyl, halogen, phenyl, Phenyl, cyano, nitro, pyridyl, pyrazolyl substituted by at least one group in combination A, pyrazolyl substituted by at least one group in combination A, and R 1 , R 2 , at least one of R 3 and R 4 is a C 1 -C 12 alkoxy group or a C 1 -C 12 alkylthio group; or, R 2 and R 3 are cyclized together to form an unsubstituted or unsubstituted group from combination A.
  • the combination A consists of a C 1 -C 12 alkyl group, a halogen, a C 1 -C 12 alkyl group substituted by at least one halogen, and a C 1 -C 12 alkoxy group.
  • the second aspect of the present invention provides a method for preparing the compound containing a chain carboxylic acid amide structure described in the first aspect or its agrochemically acceptable salt, hydrate and solvate, which method includes: condensation Under the reaction conditions, the compound represented by formula (II) and the compound represented by formula (III) are contacted and reacted,
  • the third aspect of the present invention provides the use of the compound containing a chain carboxylic acid amide structure described in the first aspect or its agrochemically acceptable salts, hydrates and solvates in preventing and controlling plant oomycete diseases.
  • the fourth aspect of the present invention provides the use of the compound containing a chain carboxylic acid amide structure described in the first aspect or its agrochemically acceptable salt, hydrate and solvate as an agricultural fungicide.
  • the fifth aspect of the present invention provides a fungicide, which is composed of active ingredients and auxiliary materials.
  • the active ingredients include the compound containing a chain carboxylic acid amide structure described in the first aspect or an agrochemically acceptable compound thereof. Salts, Hydrates and Solvates.
  • the compound of the present invention has excellent control effect on plant diseases caused by oomycetes such as cucumber downy mildew, Phytophthora infestans, and Phytophthora capsici. It is equivalent to the current commercial oomycete disease control agent fluthiazole pyriacetophenone and has good efficacy. Market development prospects.
  • Halogen means fluorine, chlorine, bromine, and iodine.
  • C 1 -C 12 alkyl group means an alkyl group with a total number of carbon atoms of 1-12, including straight-chain alkyl groups and branched-chain alkyl groups. For example, it can be an alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5,
  • the linear alkyl and branched alkyl groups of 6, 7, 8, 9, 10, 11 and 12 can be, for example, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. ;
  • the definition of "C 1 -C 10 alkyl group” is similar to the definition of "C 1 -C 12 alkyl group", except that the total number of carbon atoms is different.
  • C 1 -C 12 alkoxy group is similar to the definition of "C 1 -C 12 alkyl group”. The difference is that "C 1 -C 12 alkoxy group” is directly connected to the parent core through an O atom. , represents an alkoxy group with a total number of carbon atoms of 1-12, including linear alkoxy groups and branched chain alkoxy groups, for example, it can be an alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8,
  • the linear alkoxy group and branched chain alkoxy group of 9, 10, 11, and 12 can be, for example, methyloxy, ethyloxy, n-propyloxy, Isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy.
  • the definition of "C 1 -C 10 alkoxy group” is similar to the definition of "
  • C 1 -C 12 alkylthio group and “C 1 -C 12 alkyl group” are similar. The difference is that “C 1 -C 12 alkylthio group” is directly connected to the parent core through the S atom, which means Alkylthio groups with a total number of carbon atoms of 1 to 12 include straight-chain alkylthio groups and branched-chain alkylthio groups.
  • the linear alkylthio group and branched chain alkylthio group of 10, 11, and 12 can be, for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, or n-butylthio group.
  • base isobutylthio group, tert-butylthio group, n-pentylthio group, isopentylthio group, n-hexylthio group.
  • the definition of "C 1 -C 10 alkylthio group” is similar to the definition of "C 1 -C 12 alkylthio group", except that the total number of carbon atoms is different.
  • C 3 -C 12 cycloalkyl means a cycloalkyl group with a total number of carbon atoms of 3-12, and the ring atoms are all C atoms.
  • the total number of ring carbon atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and any position that can be substituted on the "C 3 -C 12 cycloalkyl group" is directly connected to the mother core.
  • the definition of "C 3 -C 10 cycloalkyl” is similar to the definition of "C 3 -C 12 cycloalkyl", except that the total number of carbon atoms is different.
  • C 1 -C 12 alkoxy group substituted by at least one halogen means that at least one H atom in the "C 1 -C 12 alkoxy group" is substituted by halogen, and the substituted halogen can be one or more .
  • C 1 -C 10 alkoxy substituted by at least one halogen has a similar definition except that the total number of carbon atoms is different.
  • C 1 -C 12 alkyl group substituted by at least one halogen means that at least one H atom in the "C 1 -C 12 alkyl group” is substituted by halogen, and the substituted halogen may be one or more.
  • C 1 -C 10 alkyl substituted by at least one halogen has a similar definition except that the total number of carbon atoms is different.
  • C 1 -C 12 alkoxy group substituted by phenyl group means that at least one H atom in the “C 1 -C 12 alkoxy group” is substituted by phenyl group.
  • C 1 -C 10 alkoxy substituted by phenyl has a similar definition, except that the total number of carbon atoms is different.
  • R 2 and R 3 cyclize together to form a 3-7-membered saturated heterocyclyl group that is unsubstituted or substituted by at least one group in combination A and contains at least one O atom as a ring-forming atom
  • R 2 and R 3 cyclize together to form a 3-7-membered saturated heterocyclyl group that is unsubstituted or substituted by at least one group in combination A and contains at least one O atom as a ring-forming atom
  • the total number is 3, 4, 5, 6, 7 and contains at least one O atom.
  • a group "substituted by at least one group in combination A” means that at least one group in combination A can be substituted at any position that can be substituted.
  • the dotted line in the structural formula shown by the group indicates the connection position between the group and the parent core.
  • the first aspect of the present invention provides a compound containing a chain carboxylic acid amide structure or an agrochemically acceptable salt, hydrate and solvate thereof, the compound having formula (I) structure.
  • One of X 1 and X 2 is S and the other is CH;
  • R is a structure represented by formula (Q1); in formula (Q1), R 1 , R 2 , and R 3 are each independently selected from H, a C 1 -C 12 alkyl group, and a C 1 -C 12 alkoxy group. group, C 3 -C 12 cycloalkyl group, C 1 -C 12 alkylthio group, C 1 -C 12 alkoxy group substituted by at least one halogen, C 1 -C 12 alkyl group substituted by phenyl Oxygen, halogen, phenyl, phenyl substituted by at least one group in combination A, cyano group, nitro, pyridyl, pyrazolyl, pyrazole substituted by at least one group in combination A group; alternatively, R 2 and R 3 are cyclized together to form a 3-7-membered saturated heterocyclic group that is unsubstituted or substituted by at least one group in combination A and contains at least one O atom as a ring
  • A is N or CH; and when A is N, one of R 2 and R 3 does not exist; the combination A consists of C 1 -C 12 alkyl, halogen, C 1 - substituted by at least one halogen Composed of C 12 alkyl group and C 1 -C 12 alkoxy group.
  • one of X 1 and X 2 is S and the other is CH;
  • R is a structure represented by formula (Q1); in formula (Q1), R 1 , R 2 , and R 3 are each independently selected from H, a C 1 -C 10 alkyl group, and a C 1 -C 10 alkoxy group. group, C 3 -C 10 cycloalkyl group, C 1 -C 10 alkylthio group, C 1 -C 10 alkoxy group substituted by at least one halogen, C 1 -C 10 alkyl group substituted by phenyl Oxygen, halogen, phenyl, phenyl substituted by at least one group in combination A, cyano group, nitro, pyridyl, pyrazolyl, pyrazole substituted by at least one group in combination A group; alternatively, R 2 and R 3 are cyclized together to form a 3-7-membered saturated heterocyclic group that is unsubstituted or substituted by at least one group in the combination A and contains at least one O atom as a
  • the combination A consists of a C 1 -C 10 alkyl group, a halogen, a C 1 -C 10 alkyl group substituted by at least one halogen, and a C 1 -C 10 alkoxy group.
  • the compound of the structure represented by formula (I) is selected from any one of the following:
  • One of X 1 and X 2 is S and the other is CH;
  • R is a structure represented by formula (Q2);
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group, C 3 -C 12 cycloalkyl, C 1 -C 12 alkylthio, C 1 -C 12 alkoxy substituted by at least one halogen, C 1 -C 12 alkoxy substituted by phenyl, halogen , phenyl, phenyl, cyano, nitro, pyridyl, pyrazolyl, pyrazolyl substituted by at least one group in combination A; and R 1.
  • At least one of R 2 , R 3 and R 4 is a C 1 -C 12 alkoxy group or a C 1 -C 12 alkylthio group, or R 2 and R 3 are cyclized together to form an unsubstituted or A 3-7 membered saturated heterocyclic group containing at least one O atom substituted by at least one group in combination A;
  • the combination A consists of a C 1 -C 12 alkyl group, a halogen, a C 1 -C 12 alkyl group substituted by at least one halogen, and a C 1 -C 12 alkoxy group.
  • one of X 1 and X 2 is S and the other is CH;
  • R is a structure represented by formula (Q2);
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 10 alkyl group, C 1 -C 10 alkoxy group, C 3 -C 10 cycloalkyl, C 1 -C 10 alkylthio, C 1 -C 10 alkoxy substituted by at least one halogen, C 1 -C 10 alkoxy substituted by phenyl, halogen , phenyl, phenyl, cyano, nitro, pyridyl, pyrazolyl, pyrazolyl substituted by at least one group in combination A; and R 1.
  • At least one of R 2 , R 3 and R 4 is a C 1 -C 10 alkoxy group or a C 1 -C 10 alkylthio group, or R 2 and R 3 are cyclized together to form an unsubstituted or A 3-7-membered saturated heterocyclic group containing at least one O atom substituted by at least one group in the combination A; the combination A consists of a C 1 -C 10 alkyl group, halogen, C substituted by at least one halogen Composed of 1 -C 10 alkyl group and C 1 -C 10 alkoxy group.
  • the compound of the structure represented by formula (I) is selected from any one of the following:
  • the stereostructure of the compound represented by the formula (I) there is no particular restriction on the stereostructure of the compound represented by the formula (I).
  • the compound represented by the formula (I) can be expressed as different stereoisomers or optical isomers or tautomeric forms.
  • the present invention encompasses all stereoisomers or optical isomers or tautomers and mixtures thereof in all ratios.
  • Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention may exist in a racemic or enantioenriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • the present invention has no special restrictions on the method for preparing the compound containing a chain carboxylic acid amide structure. Those skilled in the art can prepare it through the characteristics of the structural formula in combination with known methods in the field of organic synthesis. However, in order to achieve higher yields, Efficiently obtain the compound containing the chain carboxylic acid amide structure of the present invention or its agrochemically acceptable salt, hydrate and solvate.
  • the present invention provides the method described in the second aspect below to prepare the chain carboxylic acid-containing compound.
  • Compounds with an amide structure or agrochemically acceptable salts, hydrates and solvates thereof; the method includes:
  • the condensation reaction is carried out in the presence of an alkaline reagent and in an anhydrous environment.
  • the alkaline reagent is at least one of triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine.
  • the condensation reaction of the present invention is carried out under alkaline conditions.
  • the contact reaction is carried out in the presence of a solvent, and the solvent is preferably selected from at least one selected from dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile and acetone.
  • the solvent is preferably selected from at least one selected from dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile and acetone.
  • the conditions for the contact reaction include: the reaction temperature is -5°C to 60°C, and the reaction time is 1 to 48 hours.
  • the compound represented by the formula (II) and the compound represented by the formula (III) can be purchased from a commercial source, or can be synthesized according to the structural formula using methods of the prior art.
  • the present invention exemplarily provides methods for preparing compounds represented by formula (II) in the examples, which should not be understood by those skilled in the art as limitations of the present invention.
  • the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1: (1-3); more preferably, it is 1: (1.1-3) 2.2).
  • the product obtained after the contact reaction can also be subjected to post-treatment methods commonly used in the art to obtain products with higher purity.
  • the post-treatment operation method includes: extraction , washing, rotary evaporation, column chromatography, recrystallization, etc.
  • the present invention is not particularly limited, as long as the compound containing the chain carboxylic acid amide structure of the present invention can be obtained.
  • the third aspect of the present invention provides the use of the compound containing a chain carboxylic acid amide structure described in the first aspect or its agrochemically acceptable salts, hydrates and solvates in preventing and treating plant oomycete diseases. applications in.
  • the plant oomycete disease is selected from at least one of cucumber downy mildew, potato late blight, and pepper Phytophthora.
  • the fourth aspect of the present invention provides the application of the compound containing a chain carboxylic acid amide structure described in the first aspect or its agrochemically acceptable salts, hydrates and solvates as agricultural fungicides. .
  • the fifth aspect of the present invention provides a bactericide, which is composed of active ingredients and auxiliary materials.
  • the active ingredients include the compound containing a chain carboxylic acid amide structure described in the first aspect or At least one of its agrochemically acceptable salts, hydrates and solvates.
  • the content of the active ingredient is 1-99.9% by weight; more preferably, the content of the active ingredient is 5-95% by weight.
  • the dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspending agent, wettable powder, powder, granule, aqueous agent, poisonous bait, mother liquor and mother powder.
  • the auxiliary materials can be various auxiliary materials commonly used in this field, such as surfactants, solvents, etc.
  • This example is used to illustrate the synthesis method of the target compound represented by formula (I-1) to formula (I-236).
  • trans-3-methoxyacrylic acid (11.4mmol, 1.4eq.) into a 100mL eggplant-shaped flask, dissolve it in 20mL dichloromethane, and add EDCI (2.1mmol, 2.1eq.) and HOBt in sequence. (2.10mmol, 2.1eq.), TEA (0.42mL, 3.0mmol, 3.0eq.), stir and activate for 60 minutes, and then add the compound represented by formula (2-5-1) (1.0mmol, 1.0eq.) to the system. .
  • the relevant acid intermediates can be obtained by directly hydrolyzing the esters.
  • the above synthetic route is used to first obtain the corresponding ester, and then hydrolyze to obtain the acid fragment.
  • the above-mentioned synthetic route is used to first obtain the corresponding ester, and then hydrolyze to obtain the acid fragment.
  • the zinc powder was removed by silica gel suction filtration, and washed with methylene chloride.
  • Position 2 of acrylic acid is an acid fragment modified with a substituted benzene ring.
  • the brominated compound is first obtained, and then is coupled with phenylboronic acid through Suzuki coupling to obtain the corresponding ester, and then hydrolyzed to obtain the acid fragment.
  • the carboxylic acid intermediate containing methoxime structure is introduced using the above-mentioned synthesis route, starting from substituted methyl acetoformate, reacting with methoxyamine hydrochloride to introduce the methoxime structure, and then hydrolyzing to obtain the acid fragment.
  • This example is used to illustrate the synthesis method of the target compound represented by formula (II-1) to formula (II-136).
  • carboxylic acid 3,3-dimethoxypropionic acid (1.0mmol, 1.0eq.) to a 100mL eggplant-shaped flask, dissolve it in 20mL dichloromethane, and add EDCI (1.5mmol, 1.5eq.) in sequence. .), HOBt (1.5mmol, 1.5eq.), TEA (2.1mmol, 2.14eq.), stir and activate for 60 minutes, and then add the intermediate represented by formula (2-5-1) obtained earlier to the system (0.71mmol ,0.71eq.).
  • Test Example 1 In vivo activity to inhibit cucumber downy mildew
  • test and investigation methods refer to SOP-SC-1098 Potted Cucumber Downy Mildew Method in the Fungicide Volume of the "Standard Operating Specifications for Pesticide Biological Activity Testing" written by Kang Zhuo and Gu Baogen.
  • the test results are shown in Table 1, Table 2, and Table 3.
  • the "/" item in the table indicates that it has not been tested (the situations below are the same).
  • the structural formula of the control agent fluthiazolpyridinone (OXA) is as follows:
  • Table 1 Indoor bactericidal activity of target compounds against cucumber downy mildew
  • the present invention sterilized some compounds with a control effect exceeding 75% at the lowest concentration (1.25 mg/L) initially screened in the indoor in vivo bactericidal activity test of cucumber downy mildew at reduced concentrations. Activity rescreening experiment. The experimental results are shown in Table 2.
  • Test Example 2 In vitro activity in inhibiting the growth of oomycete pathogenic fungi hyphae
  • the microplate method was used to measure the biological activity of pharmaceuticals in the laboratory.
  • Culture of Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, and Phytophthora tobacco Inoculate the target bacteria into PDB or V8 juice liquid medium and shake culture for 72-96 hours, collect fresh mycelium after filtration, and then weigh 0.1 g mycelium, put 50 ml of PDB liquid culture medium into it, use a tissue masher to mash the mycelium into small mycelial segments, make a mycelial segment suspension, and place it at 4°C for later use.
  • Culture of Phytophthora infestans Inoculate Phytophthora infestans on a V8 medium plate and culture it for 12 days. After a large number of sporangia are produced, add sterile water and transfer the plate to a 4°C refrigerator for 1 hour, and then transfer it to At room temperature, zoospore release is induced. After the zoospores are fully released, prepare a spore suspension with a spore concentration of 10 5 /mL and place it at 4°C for later use.
  • test reagent with DMSO into a 2000 mg/L stock solution, then dilute it with sterile water into a series of gradient concentration solutions, and place at 4°C for later use.
  • Inhibition rate % (Blank treatment OD 595 - Chemical treatment OD 595 )/(Blank treatment OD 595 - Reference OD 595 )*100
  • Inhibitory activity level 90% ⁇ A ⁇ 100%; 75% ⁇ B ⁇ 90%; 60% ⁇ C ⁇ 75%;
  • Test Example 3 Field efficacy test for preventing and controlling cucumber downy mildew
  • Test results show that compound II-3 has a good effect in controlling cucumber downy mildew. It can effectively protect new leaves and effectively inhibit the spread of lesions on already infected leaves.
  • the dosage is 50 mg/L. Continuous application 2 to 3 times at intervals of 5 to 7 days can effectively control the occurrence of downy mildew.
  • the preventive effect is better than that of the control drugs OXA and silverfari.
  • Test Example 4 Field efficacy test for preventing and controlling potato late blight
  • the survey method is to sample at five diagonal points in each plot, select two plants at each point, and survey about 20 middle and upper leaves of each plant. Record the total number of leaves investigated, the number of diseased leaves and the number of disease stages, and calculate the disease index and control effect. The results are shown in Table 6.

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Abstract

本发明涉及农药杀菌剂领域，公开了含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂，该化合物具有式(I)所示的结构。本发明的化合物对黄瓜霜霉菌、致病疫霉菌、辣椒疫霉菌等卵菌引起的植物病害具有优异的防治效果，与目前商品化卵菌病害防治药剂氟噻唑吡乙酮相当，具有很好的市场开发前景。

Description

含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂
相关申请的交叉引用
本申请要求2022年08月26日提交的中国专利申请202211035626.7的权益，该申请的内容通过引用被合并于本文。
技术领域
本发明涉及农药杀菌剂领域，具体涉及含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂。
背景技术
卵菌是引起植物病害的重要病原菌之一，具有寄生范围广、破坏性强、为害性大、发展迅速等特点。
霜霉菌是最具代表性的卵菌之一，其潜伏期短、可多次侵染，在极短的时间内可导致病害大流行，如该病菌引起的黄瓜霜霉病可以在短短几日内导致黄瓜全部死亡。
一般霜霉菌引起的植物病害可分为以下三类：1)叶病，主要是霜霉病；2)一年生和多年生作物的根和冠病，如土壤潮湿、幼苗枯萎、根、颈和茎腐病；3)全身性疾病，是指由土壤或种子的根部感染、病原体在植物的维管系统中的分布以及症状在生长点或叶片上的表现所引起的疾病。
在温带和热带气候中，大多数一年生或多年生的农业、园艺和观赏作物(如葡萄、黄瓜、马铃薯、烟草、番茄、啤酒花、柑橘、向日葵、蔬菜和大豆)，都可能受到霜霉菌的侵袭，这使得霜霉菌成为一类极具破坏性的植物病原体，其引起的病害也较难防治，因此给农业生产带来极大的损失。长期以来，有效控制它们一直是优先考虑的问题。
卵菌病害防治日益困难，目前，化学防治依旧是防治举措中最为简便和有效的方法，生产上主要使用的是多作用位点的保护性杀菌剂和单作用位点的内吸性杀菌剂。但随着这些杀菌剂使用时间的延长和长期的不合理使用，使得很多病原菌出现了严重的抗药性。
因此，开发新型的与传统杀菌剂无交互抗性的卵菌杀菌剂成为目前该领域所急需的发展方向。
发明内容
本发明的目的是为了克服现有技术的前述缺陷，提供一类新型的与传统杀菌剂无交互抗性的卵菌杀菌剂。
为了实现上述目的，本发明的第一方面提供一种含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，该化合物具有式(I)所示的结构，
其中，在式(I)中，X1和X2中的一者为S，另一者为CH；
R为式(Q1)所示的结构或式(Q2)所示的结构；
在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中 的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；A为N或CH；且当A为N时，R2和R3中的一者不存在；
在式(Q2)中，R1、R2、R3、R4各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基，且R1、R2、R3、R4中的至少一者为C1-C12的烷氧基或C1-C12的烷硫基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成。
本发明的第二方面提供一种制备第一方面中所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物的方法，该方法包括：在缩合反应条件下，将式(II)所示的化合物与式(III)所示的化合物进行接触反应，
且式(II)所示的化合物与式(III)所示的化合物中的取代基的定义与第一方面中所述的定义相同。
本发明的第三方面提供第一方面中所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物在防治植物卵菌病害中的应用。
本发明的第四方面提供第一方面中所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物作为农用杀菌剂的应用。
本发明的第五方面提供一种杀菌剂，该杀菌剂由活性成分和辅料组成，所述活性成分包括第一方面所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物。
本发明的化合物对黄瓜霜霉菌、致病疫霉菌、辣椒疫霉菌等卵菌引起的植物病害具有优异的防治效果，与目前商品化卵菌病害防治药剂氟噻唑吡乙酮相当，具有很好的市场开发前景。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
以下针对本发明的部分基团提供一些示例性的解释，在没有特别说明的情况下，未列举的部分参照如下示例性的解释进行解释。
“卤素”表示氟、氯、溴、碘。
“C1-C12的烷基”表示碳原子总数为1-12的烷基，包括直链烷基、支链烷基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9、10、11、12的直链烷基、支链烷基，例如可以为正丁基、异丁基、叔丁基、正戊基、异戊基、正己基等；“C1-C10的烷基”的定义与“C1-C12烷基”的定义相似，不同的是，碳原子总数不同。
“C1-C12的烷氧基”的定义与“C1-C12烷基”的定义相似，不同的是，“C1-C12的烷氧基”通过O原子直接与母核连接，表示碳原子总数为1-12的烷氧基，包括直链烷氧基、支链烷氧基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9、10、11、12的直链烷氧基、支链烷氧基，示例性地，可以为甲基氧基、乙基氧基、正丙基氧基、 异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基、异戊基氧基、正己基氧基。“C1-C10的烷氧基”的定义与“C1-C12的烷氧基”的定义相似，不同的是，碳原子总数不同。
“C1-C12的烷硫基”与“C1-C12烷基”的定义相似，不同的是，“C1-C12的烷硫基”通过S原子直接与母核连接，表示碳原子总数为1-12的烷硫基，包括直链烷硫基、支链烷硫基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9、10、11、12的直链烷硫基、支链烷硫基，示例性地，可以为甲基硫基、乙基硫基、正丙基硫基、异丙基硫基、正丁基硫基、异丁基硫基、叔丁基硫基、正戊基硫基、异戊基硫基、正己基硫基。“C1-C10的烷硫基”的定义与“C1-C12的烷硫基”的定义相似，不同的是，碳原子总数不同。
“C3-C12的环烷基”表示碳原子总数为3-12的环烷基，且成环原子均为C原子，例如可以为成环碳原子总数为3、4、5、6、7、8、9、10、11、12，且所述“C3-C12的环烷基”上任意能够被取代的位置直接与母核连接。“C3-C10的环烷基”的定义与“C3-C12的环烷基”的定义相似，不同的是，碳原子总数不同。
“由至少一个卤素取代的C1-C12的烷氧基”表示“C1-C12的烷氧基”中的至少一个H原子由卤素取代，且取代的卤素可以为一种或者多种。“由至少一个卤素取代的C1-C10的烷氧基”具有与其相似的定义，仅仅是碳原子总数不同而已。
“由至少一个卤素取代的C1-C12的烷基”表示“C1-C12的烷基”中的至少一个H原子由卤素取代，且取代的卤素可以为一种或者多种。“由至少一个卤素取代的C1-C10的烷基”具有与其相似的定义，仅仅是碳原子总数不同而已。
“由苯基取代的C1-C12的烷氧基”表示“C1-C12的烷氧基”中的至少一个H原子由苯基取代。“由苯基取代的C1-C10的烷氧基”具有与其相似的定义，仅仅是碳原子总数不同而已。
“R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基”表示其中成环碳原子总数为3、4、5、6、7且含有至少一个O原子。
在没有特别说明的情况下，“由组合A中的至少一种基团取代的”基团，表示组合A中的至少一种基团能够在任意能够被取代的位置进行取代。基团所示的结构式中的虚线表示基团与母核之间的连接位置。
如前所述，本发明的第一方面提供了一种含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，该化合物具有式(I)所示的结构。
根据一种优选的具体实施方式，在式(I)中，
X1和X2中的一者为S，另一者为CH；
R为式(Q1)所示的结构；在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
A为N或CH；且当A为N时，R2和R3中的一者不存在；所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成。
根据另一种优选的具体实施方式，在式(I)中，X1和X2中的一者为S，另一者为CH；
R为式(Q1)所示的结构；在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C10的烷基、C1-C10的烷氧基、C3-C10的环烷基、C1-C10的烷硫基、由至少一个卤素取代的C1-C10的烷氧基、由苯基取代的C1-C10的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；A为N或CH；且当A为N时，R2和R3中的一者不存在；
所述组合A由C1-C10的烷基、卤素、由至少一个卤素取代的C1-C10的烷基、C1-C10的烷氧基组成。
根据一种特别优选的具体实施方式，式(I)所示结构的化合物选自以下中的任意一种：













根据一种优选的具体实施方式，在式(I)中，
X1和X2中的一者为S，另一者为CH；
R为式(Q2)所示的结构；R1、R2、R3、R4各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；且R1、R2、R3、R4中的至少一者为C1-C12的烷氧基或C1-C12的烷硫基，或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子的3-7元饱和杂环基；
所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成。
根据另一种优选的具体实施方式，在式(I)中，X1和X2中的一者为S，另一者为CH；
R为式(Q2)所示的结构；R1、R2、R3、R4各自独立地选自H、C1-C10的烷基、C1-C10的烷氧基、C3-C10的环烷基、C1-C10的烷硫基、由至少一个卤素取代的C1-C10的烷氧基、由苯基取代的C1-C10的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；且R1、R2、R3、R4中的至少一者为C1-C10的烷氧基或C1-C10的烷硫基，或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子的3-7元饱和杂环基；所述组合A由C1-C10的烷基、卤素、由至少一个卤素取代的C1-C10的烷基、C1-C10的烷氧基组成。
根据另一种特别优选的具体实施方式，式(I)所示结构的化合物选自以下中的任意一种：







本发明中对所述式(I)所示的化合物的立体结构没有特别限制，所述式(I)所示的化合物可以以不同的立体异构体或光学异构体或互变异构的形式存在，本发明包含所有立体异构体或光学异构体或互变异构及其各种比例的混合物。
本发明公开化合物的任何不对称原子(例如，碳等)均可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。
本发明对制备所述含链状羧酸酰胺结构的化合物的方法没有特别的限制，本领域技术人员可以通过结构式的特征，结合有机合成领域内的已知方法制备获得，但是，为了更高收率地获得本发明所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，本发明提供如下第二方面所述的方法制备含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物；该方法包括：
在缩合反应条件下，将式(II)所示的化合物与式(III)所示的化合物进行接触反应，
且式(II)所示的化合物与式(III)所示的化合物中的取代基的定义与第一方面中所述的定义相同。
优选地，所述缩合反应在碱性试剂的存在且无水环境下进行。
优选情况下，所述碱性试剂为三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶中的至少一种。
本发明的所述缩合反应在碱性条件下进行。
优选地，所述接触反应在溶剂存在下进行，所述溶剂优选选自二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈和丙酮中的至少一种。
优选地，所述接触反应的条件包括：反应温度为-5℃至60℃，反应时间为1～48h。
在本发明中，所述式(II)所示的化合物与式(III)所示的化合物可以来自商购，也可以根据结构式而采用现有技术的方法合成得到。本发明在实施例中示例性地提供了制备式(II)所示的化合物的方法，本领域技术人员不应理解为对本发明的限制。
优选地，在本发明的第二方面中，式(II)所示的化合物与式(III)所示的化合物的用量摩尔比为1：(1～3)；更优选为1：(1.1～2.2)。
在本发明的第二方面中，还可以对接触反应后获得的产物进行本领域内常规应用的后处理方法进行后处理以获得纯度更高的产物，例如，所述后处理操作方法包括：萃取、洗涤、旋转蒸发、柱层析、重结晶等，本发明对此没有特别的限制，只要能够获得本发明前述含链状羧酸酰胺结构的化合物即可。
如前所述，本发明的第三方面提供了第一方面中所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物在防治植物卵菌病害中的应用。
优选地，所述植物卵菌病害选自黄瓜霜霉病、马铃薯晚疫病、辣椒疫霉病中的至少一种。
如前所述，本发明的第四方面提供了前述第一方面所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物作为农用杀菌剂的应用。
如前所述，本发明的第五方面提供了一种杀菌剂，该杀菌剂由活性成分和辅料组成，所述活性成分包括前述第一方面所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物中的至少一种。
优选地，所述活性成分的含量为1-99.9重量％；更优选所述活性成分的含量为5-95重量％。
优选地，所述杀菌剂的剂型选自乳油、悬浮剂、可湿性粉剂、粉剂、粒剂、水剂、毒饵、母液和母粉中的至少一种。
在本发明中，所述辅料可以为本领域内常规使用的各种辅料，例如可以为表面活性剂、溶剂等。
以下将通过实例对本发明进行详细描述。
以下实例中，在没有特别说明的情况下，使用的各种原料均来自商购，纯度为化学纯。
以下室温均表示25±1℃。
实施例1
式(2-2)的合成：25℃下，取式(2-1)所示化合物(790.12mmol)置于1L两颈烧瓶中，加入400mL的2M的盐酸乙醚溶液中，向反应瓶中缓慢滴加亚硝酸特丁酯(534.62mmol)，反应3小时。反应完毕将反应混合物减压浓缩成半固体，用1-氯丁烷洗涤，抽滤得到白色晶状固体，将滤液浓缩，重复以上过程2次，合并滤出的固体，共计81.10g。直接用于下一步反应。
式(2-3)的合成：向一个500mL的梨型瓶中，依次加入磁子，式(2-2)所示化合物(193.48mmol)，250mL乙腈，碳酸氢钠(1.14mol)，开启搅拌，用恒压滴液漏斗缓慢滴加2,6-二氟苯乙烯(193.51mmol)。反应30分钟，TLC监测反应完全。将体系抽滤，滤饼用乙腈洗涤三次，合并滤液，减压浓缩，得到浅黄色粘稠液体。放置一夜后有固体析出，抽滤，将滤饼用V石油醚:V乙酸乙酯＝10:1的溶液洗涤，减压除去溶剂，得到浅黄色固体，滤液再次浓缩，有固体析出，重复上步操作两次，合并所得固体，得式(2-3)所示化合物54.39g，质谱结果显示分子离子峰259.30。核磁氢谱数据如下：1H NMR(400MHz,CDCl3)δ7.47–7.25(m,1H),6.88(t,J＝8.0Hz,2H),6.20–6.08(m,1H),4.67(s,2H),3.60–3.52(m,1H),3.33(dd,J＝17.2,8.0Hz,1H).
式(2-4)的合成：向250mL的梨型瓶中，依次加入磁子，式(2-3)所示化合物(38.51mmol)，100mL无水甲醇，搅拌下加入4-氨基硫代羰基四氢吡啶-1(2H)-甲酸叔丁酯(38.02mmol)，升温至回流，约4小时反应完毕。减压浓缩除去大部分甲醇，加入100mL水，用乙酸乙酯进行萃取，分液，有机相用无水硫酸钠干燥，过滤，滤液浓缩，经硅胶柱层析纯化得式(2-4)所示化合物,收率为89％。核磁氢谱数据如下：1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.29–7.25(m,1H),6.96(t,J＝8.0Hz,2H),6.03(dd,J＝12.0,9.2Hz,1H),4.21(s,2H),3.77(dd,J＝17.6,12.0Hz,1H),3.60(dd,J＝17.6,9.2Hz,1H),3.19(tt,J＝12.0,4.0Hz,1H),2.86(t,J＝10.4Hz,2H),2.09(d,J＝12.8Hz,2H),1.70(qd,J＝12.8,4.8Hz,2H),1.39(s,9H).
式(2-5-1)的合成：向式(2-4)所示化合物(40.0mmol)中加入80mL甲醇，使其完全溶，再加入45mL盐酸/甲醇(4M)溶液中，升温至50℃，反应4h，反应完毕，减压浓缩除去溶剂，此时产物以盐酸盐的形式存在，加入2M氢氧化钠溶液中和，使体系呈碱性，用乙酸乙酯多次萃取，有机相干燥，浓缩得黄褐色油状粗品，硅胶柱层析得到浅棕色固体，收率为95％。核磁氢谱数据如下：1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.01(s,1H),7.48–7.39(m,1H),7.20(t,J＝8.4Hz,2H),5.98(dd,J＝12.0,9.2Hz,1H),3.87(dd,J＝17.6,12.0Hz,1H),3.61–3.49(m,1H),3.41–3.37(m,3H),3.02(t,J＝12.0Hz,2H),2.19(d,J＝14.0Hz,2H),1.88(q,J＝12.4Hz,2H).
实施例2
式(2-7)的合成：将乙醛酸乙酯(50％的甲苯溶液，369mmol)和盐酸羟胺(369mmol)溶于CH3CN:H2O(9:1,300mL)中，在室温下搅拌5分钟，然后滴加Et3N(51.7mL,369mmol)。反应在室温下进行1小时，然后减压浓缩。将残渣溶于H2O(50mL)和Et2O(300mL)中。有机层用饱和NH4Cl(50mL)洗涤，用Na2SO4干燥，过滤，浓缩。得无色晶状物收率为97％。
式(2-8)的合成：在5℃条件下，将(2)-(羟基亚胺)乙酸乙酯(123.2mmol)加入到DMF溶液中。反应混合物在室温下搅拌12小时，加入水(200mL)，用乙酸乙酯(2×150mL)萃取。分离有机层，用无水硫酸钠干燥，减压浓缩得到粗产物，收率为74％。
式(2-9)的合成：向500mL的梨型瓶中，依次加入磁子，式(2-8)所示化合物(1.52g)，250mL乙腈，碳酸氢钠(5.04g)，开启搅拌，用恒压滴液漏斗缓慢滴加2,6-二氟苯乙烯(1.4g)。反应30分钟，TLC监测反应完全。将体系抽滤，滤饼用乙腈洗涤三次，合并滤液，减压浓缩，得到浅黄色粘稠液体。放置一夜后有固体析出，抽滤，将滤饼用V石油醚:V乙酸乙酯＝10:1的溶液洗涤，减压除去溶剂，得到浅黄色固体，滤液再次浓缩，有固体析出，重复上步操作两次，合并所得固体，得式(2-9)所示化合物。
式(2-10)的合成：将式(2-9)所示化合物置于封管中，用乙醇溶解，加入一水合氨(5eq.)。室温反应24小时，反应完毕，有固体析出，抽滤，将滤饼用V石油醚:V乙酸乙酯＝10:1的溶液洗涤，收集滤饼，干燥得白色固体。
式(2-11)的合成：将式(2-10)所示化合物(1.8g)溶于无水四氢呋喃中，加入五硫化二磷(3.55g)，50℃反应6小时。然后加入乙酸乙酯和1N盐酸，将得到的悬浮液过滤。用水和乙酸乙酯洗涤残渣，得到式(2-11)所示化合物。
式(2-5-2)的合成：将式2-11所示化合物(1.69g)，溶于甲醇中，加入式(2-12)所示化合物(2.14g)，回流6小时。反应完毕冷至室温，加入浓盐酸3mL，TLC监测至反应完全。向体系中加入2M氢氧化钠溶液，将体系调pH至10，用二氯甲烷萃取，无水硫酸钠干燥，浓缩，得黄褐色油状物式(2-5-2)。
实施例3：制备式(I)所示的化合物
本实施例用于说明式(Ⅰ-1)～式(Ⅰ-236)所示目标化合物的合成方法。
具体地，以式(Ⅰ-1)所示化合物的制备为例：
室温条件下，向100mL的茄形瓶中，加入反-3-甲氧基丙烯酸(1.4mmol,1.4eq.)，用20mL二氯甲烷溶解，依次加入EDCI(2.1mmol,2.1eq.)，HOBt(2.10mmol,2.1eq.)，TEA(0.42mL,3.0mmol,3.0eq.)，搅拌活化60min，再向体系中加入式(2-5-1)所示化合物(1.0mmol,1.0eq.)。继续反应6h，反应完毕加水，二氯甲烷萃取2次，有机相干燥，浓缩拌样，柱层析纯化(V石油醚:V乙酸乙酯＝2:1)，得到目标化合物式(Ⅰ-1)。白色固体，收率78％。
实施例4
酸中间体Ⅰ-1a～Ⅰ-5a的合成路线和方法
针对部分酸对应酯的片段，直接进行酯水解即可得到相关酸中间体。
以式(Ⅰ-1a)所示化合物的合成方法为例：取50mL茄形瓶，加入反-3-甲氧基丙烯酸甲酯(10.0mmol,1eq.)，再加入10mL氢氧化钠溶液(20.0mmol,2.0eq.)，反应温度升至80℃，反应过夜，TLC监测水解完全，停止加热。温度降至室温后，使用2mol/L盐酸调至酸性，有白色固体析出，抽滤，少量水洗滤饼2次，收集滤饼，干燥得酸纯品，白色固体，收率56.8％。
实施例5
酸中间体Ⅰ-6a～Ⅰ-10a的合成路线和方法
对丙烯酸2号位为吸电子取代基修饰的酸片段，采用上述合成路线，先得到相应酯，再水解得到酸片段。
以化合物Ⅰ-8a的制备为例：取100mL三颈烧瓶，N2氛围下，加入20mL超干二氯甲烷，称取溴乙酸甲酯(10.0mmol,1.0eq.)，甲酸甲酯(30.0mmol,3.0eq.)溶于其中，放入低温反应器中降温至-40℃，向体系中加入三乙胺(24.0mmol,2.4eq.)，待温度重新降至-40℃后，向反应体系中缓慢滴加TiCl4(15mL,1mol/L于DCM中,15.0mmol,1.5eq.)，滴加完毕后，继续反应10min，升温至5℃继续反应1h，反应完毕，将反应混合物倒入冰水中，二氯甲烷萃取两遍，有机相干燥，浓缩拌样，柱层析纯化(V石油醚:V乙酸乙酯＝20:1)，得黄色油状化合物，收率76.7％。水解酸化得相应酸Ⅰ-8a。
实施例6
酸中间体Ⅰ-11a～Ⅰ-14a的合成路线和方法
对丙烯酸2号位为甲基等给电子取代基修饰的酸片段，采用上述的合成路线，先得到相应酯，再水解得到酸片段。
以化合物Ⅰ-11a的制备为例：准备50mL茄形瓶，加入锌粉(90.0mmol,3.0eq.)，15mL乙醚，搅拌制得悬浊液，再向恒压滴液漏斗中加入二氯甲基甲醚(30mmol,1.0eq.)、2-溴丙酸乙酯(60.0mmol,2.0eq.)，15mL乙醚溶解进行稀释。控制温度使乙醚回流，将混合物缓慢滴加茄形瓶中，滴加完毕后，继续回流反应液20min，停止反应。硅胶抽滤除去锌粉，二氯甲烷洗涤干净，滤液使用5v％醋酸-水溶液洗一次，水洗两次，饱和食盐水洗涤干燥，有机相拌样，硅胶柱层析(V石油醚:V乙酸乙酯＝10:1)，得透明油状化合物，收率57％。水解酸化得相应酸Ⅰ-11a。
实施例7
酸中间体Ⅰ-15a～Ⅰ-19a的合成路线和方法，以酸片段化合物Ⅰ-15a的合成路线和方法为例：
对丙烯酸2号位为取代苯环修饰的酸片段，采用上述的合成路线，先得溴代化合物，再与苯硼酸经Suzuki偶联得到相应酯，再水解得到酸片段。
以化合物Ⅰ-15a的制备为例：取100mL的三颈烧瓶，氮气氛围下，加入化合物甲基-(Z)-2-溴-3-甲氧基丙烯酸酯(10.0mmol,1.0eq.)、邻甲基苯硼酸(30.0mmol,3.0eq.)、无水碳酸钾(50.0mmol,5.0eq.)、双三苯基磷二氯化钯(1.0mmol,0.1eq.)，40mL异丙醇，升温至回流，反应过夜，TLC监测反应完毕，加水，乙酸乙酯萃取两次，有机相干燥，浓缩拌样，柱层析纯化(V石油醚:V乙酸乙酯＝20:1)，得淡黄色油状化合物，收率92.1％，进而水解酸化得相应酸Ⅰ-15a。
实施例8
酸中间体Ⅰ-20a～Ⅰ-25a的合成路线和方法，以酸片段化合物Ⅰ-20a的合成路线和方法为例：
羧酸中间体含甲氧肟结构的引入，采用上述的合成路线，从取代乙酰甲酸甲酯出发，与甲氧胺盐酸盐反应引入甲氧肟结构，再水解得到酸片段。
以化合物Ⅰ-20a的制备为例：取50mL茄形瓶，加入苯乙酰基乙酸甲酯(11.0mmol,1.0eq.)，甲氧胺盐酸盐(22.0mmol,2.0eq.)，20mL甲醇，体系升温至回流，继续反应8h，反应完毕加水，乙酸乙酯萃取，有机相干燥，浓缩拌样，柱层析纯化(V石油醚:V乙酸乙酯＝20:1)，得白色固体化合物，收率70.6％。进而水解酸化得相应酸Ⅰ-20a。
实施例9
本实施例用于说明式(Ⅱ-1)～式(Ⅱ-136)所示目标化合物的合成方法。
具体地，以式(II-1)所示化合物的制备为例：
室温条件下，向100mL的茄形瓶中，加入羧酸3,3-二甲氧基丙酸(1.0mmol,1.0eq.)，用20mL二氯甲烷溶解，依次加入EDCI(1.5mmol,1.5eq.)，HOBt(1.5mmol,1.5eq.)，TEA(2.1mmol,2.14eq.)，搅拌活化60min，再向体系中加入前期得到的式(2-5-1)所示中间体(0.71mmol,0.71eq.)。继续反应6h，反应完毕加水，二氯甲烷萃取，有机相干燥，浓缩拌样，柱层析纯化(V石油醚:V乙酸乙酯＝2:1)，得到目标化合物II-1。白色固体，收率68％。
实施例10
酸中间体Ⅱ-1a～Ⅱ-4a的合成路线和方法，以化合物Ⅱ-1a的合成路线和方法为例：
酸中间体Ⅱ-1a～Ⅱ-4a的合成路线和方法，以化合物Ⅱ-1a为例：
取50ml茄形瓶，加入乙基-3,3-二甲氧基丙酸酯(10.0mmol,1eq.)，再加入2mol/L的氢氧化钠溶液10mL(20.0mmol,2.0eq.)，加入30mL甲醇，使体系呈均相，反应过夜，TLC监测水解完全，停止加热。温度降至室温后，使用2mol/L盐酸酸化，乙酸乙酯萃取，干燥浓缩得酸纯品。淡黄色油，收率85％。
实施例11
酸中间体Ⅱ-5a～Ⅱ-10a的合成路线和方法，以酸片段化合物Ⅱ-5a的合成路线和方法为例：
酸中间体Ⅱ-5a～Ⅱ-10a的合成路线和方法，以化合物Ⅱ-5a的制备为例：
50ml茄形瓶，加入乙基-(E)-3-乙氧基丙烯酸酯(10.0mmol,1eq.)，再加入配好的2mol/L的氢氧化钠溶液7.5mL(15.0mmol,1.5eq.)，加入20mL甲醇，温度升至80℃，反应过夜，TLC监测水解完全，停止加热。温度降至室温后，使用2mol/L盐酸调节pH＝3，乙酸乙酯萃取，有机相干燥，浓缩得粗品酸。透明油状，收率84％。
目标化合物的表征数据：
式(Ⅰ-1).白色固体；m.p.＝134-136℃.1H NMR(600MHz,DMSO-d6)δ8.02(d,J＝3.0Hz,1H),7.49(t,J＝7.8Hz,1H),7.44(d,J＝12.0Hz,1H),7.15(t,J＝9.0Hz,2H),6.00(t,J＝10.2Hz,1H),5.90(d,J＝12.0Hz,1H),4.46(s,1H),4.16(s,1H),3.89(dd,J＝16.8,12.6Hz,1H),3.67(s,3H),3.53(dd,J＝17.4,8.6Hz,1H),3.37(s,1H),3.15(d,J＝12.6Hz,1H),2.74(d,J＝12.6Hz,1H),2.08(d,J＝13.2Hz,2H),1.57(s,2H).13C NMR(100MHz,CDCl3)δ174.79,166.03,162.69,162.59,160.13(d,J＝7.6Hz),152.28,145.14,130.55(t,J＝10.5Hz),117.70,115.77(t,J＝16.1Hz),111.98-111.73(m),94.83,72.87(t,J＝3.3Hz),57.85,41.55,40.71,32.55.HRMS(MALDI)计算值C21H22F2N3O3S[M+H]+434.1344,实测值434.1342.
式(Ⅰ-2).白色固体；m.p.＝141-143℃.1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.55–7.44(m,1H),7.16(t,J＝8.4Hz,2H),6.83(d,J＝21.6Hz,1H),6.00(dd,J＝12.0,8.8Hz,1H),4.16(d,J＝13.6Hz,2H),3.90(dd,J＝17.2,12.0Hz,1H),3.80(s,3H),3.53(dd,J＝17.2,8.6Hz,1H),3.44–3.35(m,1H),3.07(t,J＝12.6Hz,2H),2.12(dd,J＝13.6,3.6Hz,2H),1.71–1.57(m,2H).13C NMR(100MHz,DMSO-d6)δ175.27,162.39(d,J＝7.9Hz),161.36,161.15,159.91(d,J＝7.8Hz),152.58,144.78,141.29,141.22,140.18,137.65,131.83(t,J＝10.8Hz),120.34,116.09(t,J＝16.6Hz),112.78-112.53(m),72.50(d,J＝3.0Hz),61.85,44.33,41.61,32.70.HRMS(MALDI)计算值C21H21F3N3O3S[M+H]+452.1250,实测值452.1250.
式(Ⅰ-3).白色固体；m.p.＝126-128℃.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.38–7.31(m,1H),7.01(s,1H),6.99–6.91(m,2H),6.11(dd,J＝12.0,9.2Hz,1H),4.36(d,J＝13.6Hz,2H),3.91(s,3H),3.84(dd,J＝17.2,12.0Hz,1H),3.67(dd,J＝17.2,9.2Hz,1H),3.39–3.30(m,1H),3.15–3.04(m,2H),2.24(dd,J＝13.6,3.7Hz,2H),1.95–1.82(m,2H).13C NMR(100MHz,DMSO-d6)δ175.30,164.12,162.40(d,J＝7.7Hz),159.92(d,J＝7.8Hz),152.58,151.83,144.79,131.86(t,J＝11.0Hz),120.40,116.11(t,J＝16.5Hz),112.80-112.56(m),102.27,72.51,61.61,44.85,41.63,32.50.HRMS(MALDI)计算值C21H21ClF2N3O3S[M+H]+468.0955,实测值468.0953.
式(Ⅰ-4).白色固体；m.p.＝76-78℃.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.39–7.32(m,1H),7.04(s,1H),6.99–6.92(m,2H),6.11(dd,J＝12.0,9.2Hz,1H),4.37(d,J＝13.6Hz,2H),3.91(s,3H),3.84(dd,J＝17.2,12.0Hz,1H),3.67(dd,J＝17.2,9.2Hz,1H),3.39–3.30(m,1H),3.14–3.02(m,2H),2.24(dd,J＝13.6,3.6Hz,2H),1.94–1.83(m,2H).13C NMR(150MHz,CDCl3)δ174.47,164.93,162.18,160.52,152.25,145.16,130.55,117.74,115.73(t,J＝15.6Hz),111.92,111.77,91.57,72.85,61.39,45.06,41.53,40.46,32.27.HRMS(MALDI)计算值C21H21BrF2N3O3S[M+H]+514.0431,实测值514.0434.
式(Ⅰ-5).浅黄色固体；m.p.＝76-78℃.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.38–7.30(m,1H),6.95(t,J＝8.0Hz,2H),6.76(s,1H),6.11(dd,J＝12.0,9.2Hz,1H),4.36(d,J＝13.6Hz,2H),3.90(s,3H),3.84(dd,J＝17.2,12.0Hz,1H),3.66(dd,J＝17.2,9.2Hz,1H),3.40–3.30(m,1H),3.07(t,J＝12.0Hz,2H),2.27–2.18(m,2H),1.94–1.81(m,2H).13C NMR(100MHz,CDCl3)δ174.52,165.90,162.61(d,J＝7.5Hz),160.11(d,J＝7.7Hz),155.16,152.23,145.17,130.59(t,J＝10.6Hz),117.82,115.74(t,J＝16.2Hz),112.00-111.75(m),72.87(t,J＝2.8Hz),63.68,60.96,45.22,41.55(d,J＝2.3Hz),40.43,32.13.HRMS(MALDI)计算值C21H22F2IN3O3S[M+H]+560.0311,实测值560.0308.
式(Ⅰ-6).白色固体；m.p.＝87-89℃.1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.69(s,1H),7.35–7.28(m,1H),6.92(t,J＝8.0Hz,2H),6.08(dd,J＝12.0,9.2Hz,1H),4.84(d,J＝13.6Hz,1H),3.85–3.76(m,4H),3.73(d,J＝12.8Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.54(t,J＝12.0Hz,1H),3.48–3.35(m,2H),2.31(d,J＝13.6Hz,2H),2.09–1.94(m,2H).13C NMR(100MHz,CDCl3)δ172.92,167.29,162.62(d,J＝7.6Hz),160.12(d,J＝7.6Hz),155.65,152.13,145.38,130.62(t,J＝10.7Hz),117.95,117.92,115.73(t,J＝16.2Hz),112.02-111.77(m),72.94(t,J＝2.9 Hz),69.71,56.09,52.16,45.68,41.55,39.18,32.73,31.59.HRMS(MALDI)计算值C22H21F2N4O3S[M+H]+459.1297,实测值459.1302.
式(Ⅰ-7).黄色油状物.1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.39–7.30(m,1H),6.95(t,J＝8.0Hz,2H),6.46–6.41(m,1H),6.11(dd,J＝12.0,9.2Hz,1H),4.34(d,J＝13.6Hz,2H),3.84(dd,J＝17.2,12.0Hz,1H),3.74(s,3H),3.66(dd,J＝17.2,9.2Hz,1H),3.38–3.29(m,1H),3.10–2.98(m,2H),2.22(dd,J＝13.6,3.6Hz,2H),1.88–1.74(m,5H).13C NMR(100MHz,CDCl3)δ174.75,171.37,162.63(d,J＝7.0Hz),160.13(d,J＝7.0Hz),152.24,150.31,145.18,130.56(t,J＝10.0Hz),117.71,115.77(t,J＝16.0Hz),111.98-111.74(m),109.47,72.86(t,J＝3.0Hz),60.33,44.67,41.55,40.77,32.59,11.83.HRMS(MALDI)计算值C22H24F2N3O3S[M+H]+448.1501,实测值448.1502.
式(Ⅰ-8).黄色油状物.1H NMR(400MHz,CDCl3)δ7.68(d,J＝0.8Hz,1H),7.39–7.31(m,1H),6.95(t,J＝8.0Hz,2H),6.28(s,1H),6.11(dd,J＝12.0,9.2Hz,1H),4.42(d,J＝13.6Hz,2H),3.84(dd,J＝17.2,12.0Hz,1H),3.72(d,J＝0.8Hz,3H),3.66(dd,J＝17.2,9.2Hz,1H),3.40–3.28(m,1H),3.05(t,J＝12.0Hz,2H),2.35(q,J＝7.6Hz,2H),2.27–2.19(m,2H),1.87–1.72(m,2H),1.08–1.01(m,3H).13C NMR(100MHz,CDCl3)δ174.77,170.77,162.64(d,J＝7.0Hz),160.14(d,J＝8.0Hz),152.21,148.54,145.17,130.56(t,J＝10.0Hz),117.71,117.69,116.00,115.78(t,J＝16.0Hz),111.99-111.74(m),72.89(t,J＝3.0Hz),60.27,41.56,40.76,32.64,19.64,12.87.HRMS(MALDI)计算值C23H26F2N3O3S[M+H]+462.1657,实测值462.1660.
式(Ⅰ-9).黄色油状物.1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.35–7.25(m,1H),6.92(t,J＝8.0Hz,2H),6.28(s,1H),6.08(dd,J＝12.0,9.2Hz,1H),4.38(d,J＝13.6Hz,2H),3.81(dd,J＝17.2,12.0Hz,1H),3.68(s,3H),3.63(dd,J＝17.2,9.2Hz,1H),3.35–3.25(m,1H),3.01(s,2H),2.27(dd,J＝8.8,6.4Hz,2H),2.23–2.15(m,2H),1.82–1.69(m,2H),1.47–1.37(m,2H),0.92(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ174.78,170.93,162.63(d,J＝8.0Hz),160.13(d,J＝8.0Hz),152.23,149.03,145.18,130.56(t,J＝11.0Hz),117.73,115.77(t,J＝16.0Hz),114.70,111-111.74(m),72.87(t,J＝3.0Hz),60.25,44.70,41.54,40.78,32.62,28.38,21.64,14.10.HRMS(MALDI)计算值C24H28F2N3O3S[M+H]+476.1814,实测值476.1816.
式(Ⅰ-10).白色固体；m.p.＝58-60℃.1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.31(tt,J＝8.4,6.4Hz,1H),6.96–6.88(m,2H),6.11–6.03(m,2H),4.44(d,J＝13.2Hz,2H),3.86–3.76(m,1H),3.66(s,3H),3.65–3.59(m,1H),3.30(tt,J＝11.2,3.6Hz,1H),3.01(t,J＝12.8Hz,2H),2.86(p,J＝7.2Hz,1H),2.23–2.15(m,2H),1.81–1.67(m,2H), 1.15(s,3H),1.14(s,3H).13C NMR(100MHz,CDCl3)δ173.73,168.89,161.60(d,J＝7.3Hz),159.10(d,J＝7.5Hz),151.20,145.62,144.14,129.53(t,J＝10.6Hz),118.39,116.72,114.73(t,J＝16.1Hz),110.95-110.70(m),71.85,59.23,43.50,40.53,39.75,31.61,25.77,20.20.HRMS(MALDI)计算值C24H27F2N3NaO3S[M+Na]+:498.1633,实测值498.1632.
式(Ⅰ-11).白色固体；m.p.＝69-71℃.1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.29(d,J＝7.6Hz,1H),7.25(d,J＝4.8Hz,1H),7.26–7.20(m,3H),7.00(s,1H),6.91(t,J＝8.0Hz,2H),6.06(dd,J＝12.0,9.2Hz,1H),4.12(s,2H),3.79(s,4H),3.60(dd,J＝17.2,9.2Hz,1H),3.26–3.14(m,1H),2.86–2.74(m,2H),2.27(s,3H),1.95(d,J＝13.2Hz,2H),1.45(s,2H).13C NMR(100MHz,CDCl3)δ174.89,162.63(d,J＝8.0Hz),160.13(d,J＝8.0Hz),154.80,152.26,145.07,136.52,133.80,130.56,130.55(t,J＝10.0Hz),130.15,127.55,125.74,117.63,115.78(t,J＝16.0Hz),114.85,111.99-111.74(m),72.84(t,J＝3.0Hz),61.19,41.55,40.52,32.11,20.13.HRMS(MALDI)计算值C28H28F2N3O3S[M+H]+524.1814,实测值524.1819.
式(Ⅰ-12).白色固体；m.p.＝71-73℃.1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.36–7.24(m,3H),7.22(dd,J＝8.8,7.3Hz,1H),7.03(d,J＝7.2Hz,1H),6.91(t,J＝8.0Hz,2H),6.64(s,1H),6.06(dd,J＝12.0,9.2Hz,1H),4.26(s,2H),3.82(s,3H),3.80–3.74(m,1H),3.61(dd,J＝17.2,9.2Hz,1H),3.28–3.15(m,1H),2.96–2.84(m,2H),2.34(s,3H),2.05(s,2H),1.61(s,2H).13C NMR(100MHz,CDCl3)δ174.83,162.64(d,J＝8.0Hz),160.14(d,J＝8.0Hz),152.25,150.58,145.14,137.86,133.69,130.56(t,J＝10.0Hz),128.49,128.30,127.71,125.09,117.66,115.79(t,J＝16.0Hz),115.22,111.99-111.75(m),72.85,61.39,41.58,40.58,32.34,21.60.HRMS(MALDI)计算值C28H28F2N3O3S[M+H]+524.1814,实测值524.1819.
式(Ⅰ-13).白色固体；m.p.＝81-83℃.1H NMR(600MHz,DMSO-d6)δ8.01(s,1H),7.50(p,J＝7.2Hz,1H),7.31(d,J＝7.8Hz,2H),7.21–7.01(m,4H),6.61(s,1H),6.00(dd,J＝12.0,8.4Hz,1H),4.11(s,1H),3.89(dd,J＝17.4,12.0Hz,1H),3.78(s,3H),3.52(dd,J＝17.4,8.5Hz,1H),3.38(s,2H),2.94(t,J＝12.6Hz,2H),2.27(s,3H),2.07–1.95(m,2H),1.51(s,2H).13C NMR(150MHz,DMSO-d6)δ174.82,162.43(d,J＝8.0Hz),160.15(d,J＝7.8Hz),152.05,150.38,144.88,137.69,133.45,130.22(t,J＝10.0Hz),128.29,128.08,127.59,124.42,117.37,115.69(t,J＝16.0Hz),115.22,111.98-111.74(m),72.87(t,J＝3.0Hz),61.28,41.58,40.56,32.31,21.22.HRMS(MALDI)计算值C28H28F2N3O3S[M+H]+524.1814,实测值524.1816.
式(Ⅰ-14).白色固体；m.p.＝79-81℃.1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.34–7.27(m,1H),7.09(d,J＝7.6Hz,1H),7.05(s,1H),6.98(dd,J＝7.6,1.6Hz,1H),6.96(s,1H),6.91(t,J＝8.0Hz,2H),6.05(dd,J＝12.0,9.2Hz,1H),4.14(s,2H),3.82–3.71(m,4H),3.60(dd,J＝17.2,9.2Hz,1H),3.19–3.09(m,1H),2.84–2.75(m,2H),2.30(s,3H),2.22(s,3H),2.00–1.87(m,2H),1.45(s,2H).13C NMR(100MHz,CDCl3)δ174.98,169.86,162.64(d,J＝8.0Hz),160.14(d,J＝6.0Hz),154.61,152.27,145.07,135.05,133.53,133.33,130.47,128.44,117.61,115.79(t,J＝16.3Hz),114.80,111.99,111.75,72.85,61.15,41.55,40.57,32.15,20.98,19.67.HRMS(MALDI)计算值C29H30F2N3O3S[M+H]+538.1970,实测值538.1976.
式(Ⅰ-15).白色固体；m.p.＝94-96℃.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.36(d,J＝2.4Hz,1H),7.25–7.18(m,2H),7.12(dd,J＝8.8,2.5Hz,1H),6.89(s,1H),6.84(t,J＝8.4Hz,2H),6.00(dd,J＝12.0,9.2Hz,1H),4.15(s,2H),3.76(s,3H),3.75–3.68(m,1H),3.55(dd,J＝17.2,9.2Hz,1H),3.22–3.14(m,1H),2.90–2.79(m,2H),1.99(d,J＝11.2Hz,2H),1.53(d,J＝12.8Hz,2H).13C NMR(100MHz,CDCl3)δ174.77,168.22,162.63(d,J＝8.0Hz),160.13(d,J＝8.0Hz),155.83,152.25,145.11,134.77,132.41,131.81,131.75,130.85,130.56(t,J＝10.0Hz),128.70,117.71,115.78(t,J＝16.0Hz),111.99,111.94-111.69(m),72.86(t,J＝2.0Hz),61.62,41.57,40.54,32.16.HRMS(MALDI)计算值C27H24Cl2F2N3O3S[M+H]+578.0878,实测值578.0881.
式(Ⅰ-16).白色固体；m.p.＝119-121℃.1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.34–7.25(m,1H),6.95–6.87(m,2H),6.59(dd,J＝16.8,10.4Hz,1H),6.28(dd,J＝16.8,2.0Hz,1H),6.06(dd,J＝12.0,9.2Hz,1H),5.70(dd,J＝10.4,2.0Hz,1H),4.70(s,1H),4.18–3.98(m,1H),3.86–3.73(m,1H),3.62(dd,J＝17.2,9.2Hz,1H),3.38–3.29(m,1H),3.23(s,1H),2.87(s,1H),2.20(d,J＝12.0Hz,2H),1.85–1.73(m,2H).13C NMR(100MHz,DMSO-d6)δ175.41,164.74,162.38(d,J＝7.9Hz),159.90(d,J＝7.8Hz),152.58,144.75,131.85(t,J＝10.8Hz),128.93,127.64,120.36,116.09(t,J＝16.5Hz),112.79-112.55(m),72.52,72.49,72.46,45.21,41.61,40.02,33.20,32.33.HRMS(MALDI)计算值C20H20F2N3O2S[M+H]+404.1239,实测值404.1241.
式(Ⅰ-17).白色固体；m.p.＝78-80℃.1H NMR(400MHz,CDCl3)δ7.65(d,J＝2.8Hz,1H),7.59(d,J＝11.6Hz,1H),7.36–7.26(m,1H),6.91(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),5.68(d,J＝12.0Hz,1H),4.36(s,2H),3.95(q,J＝7.2Hz,2H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.40–3.25(m,1H),3.17–2.76(m,2H),2.18(dd,J＝13.6,3.6Hz,2H),1.85–1.70(m,2H),1.34(t,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,1H).13C NMR(100MHz,CDCl3)δ174.82,166.24,162.63(d,J＝7.5Hz),162.01,160.13(d,J＝7.5Hz),152.25,145.10,130.54(t,J＝10.6Hz),117.71,117.67,115.77(t,J＝16.2Hz),112.02–111.68(m),95.38,72.87(t,J＝2.9Hz),67.51,41.55,40.71,14.75.HRMS(MALDI)计算值C22H24F2N3O3S[M+H]+:448.1501,实测值448.1504.
式(Ⅰ-18).白色固体；m.p.＝77-79℃.1H NMR(400MHz,CDCl3)δ7.69–7.60(m,3H),7.41–7.38(m,3H),7.35–7.25(m,1H),6.98–6.87(m,2H),6.13–6.01(m,1H),4.77(dd,J＝35.2,13.6Hz,1H),4.02(d,J＝1.6Hz,3H),3.86–3.77(m,1H),3.76–3.66(m,1H),3.61(dd,J＝17.6,8.8Hz,1H),3.38–3.28(m,1H),3.32–2.93(m,2H),2.35–2.07(m,2H),1.99–1.54(m,2H).13C NMR(100MHz,CDCl3)δ174.48,163.25,162.63(d,J＝7.4Hz),160.14(d,J＝7.6Hz),152.59,152.25,145.24,130.74,130.58(t,J＝10.0Hz),130.34,128.88,128.85,126.21,126.18,117.77,115.76(t,J＝16.2Hz),111.87(d,J＝24.7Hz),111.87(d,J＝14.0Hz),72.89,62.87,46.07,41.53,40.54,40.26,32.95,31.93,29.69.HRMS(MALDI)计算值C26H25F2N4O3S[M+H]+511.1610,实测值511.1610.
式(Ⅰ-19).白色固体；m.p.＝74-76℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.36–7.17(m,5H),6.92(t,J＝8.0Hz,2H),6.08(dd,J＝12.0,9.2Hz,1H),4.67(d,J＝13.6Hz,1H),4.51–4.43(m,1H),3.94(s,3H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.31–3.41(m,2H),3.03–2.91(m,1H),2.33(s,3H),2.29–2.18(m,2H),1.93–1.80(m,2H).13C NMR(100MHz,CDCl3)δ174.50,163.76,162.65(d,J＝8.0Hz),160.15(d,J＝8.0Hz),152.26,151.50,145.22,136.49,131.04,130.59(t,J＝10.0Hz),130.27,129.38,127.29,125.55,117.80,115.78(t,J＝16.0Hz),112.01-111.76(m),72.91(t,J＝3.0Hz),62.74,46.77,41.91,41.55,40.54,32.82,31.85,20.21.HRMS(MALDI)计算值C27H27F2N4O3S[M+H]+525.1766,实测值525.1773.
式(Ⅰ-20).白色固体；m.p.＝81-83℃.1H NMR(400MHz,CDCl3)δ7.69(d,J＝11.6Hz,1H),7.55–7.40(m,2H),7.38–7.28(m,2H),7.26(s,1H),6.99–6.91(m,2H),6.15–6.06(m,1H),4.81(dd,J＝39.6,13.6Hz,1H),4.05(d,J＝1.6Hz,3H),3.84(dd,J＝17.2,10.8Hz,1H),3.79–3.71(m,1H),3.65(dt,J＝17.6,9.6Hz,1H),3.37(dt,J＝12.0,5.6Hz,1H),3.33–2.97(m,2H),2.40(s,3H),2.32(t,J＝15.6Hz,1H),2.17(dd,J＝27.6,13.2Hz,1H),2.00–1.58(m,2H).13C NMR(100MHz,CDCl3)δ174.54,163.34,162.63(d,J＝7.3Hz),160.13(d,J＝7.4Hz),152.80,152.24,145.23,138.63,131.22,130.59(t,J＝10.0Hz),128.78,128.75,126.62,123.45,117.77,115.75(t,J＝16.1Hz),112.00-111.75(m),72.89,62.65,46.11,41.52,40.58,40.26,32.97,31.97,21.43,21.41.HRMS(MALDI)计算值C27H27F2N4O3S[M+H]+525.1766,实测值525.1771.
式(Ⅰ-21).白色固体；m.p.＝85-87℃.1H NMR(400MHz,CDCl3)δ7.66(d,J＝11.2Hz,1H),7.52(dd,J＝13.2,8.0Hz,2H),7.31(q,J＝7.2Hz,1H),7.19(d,J＝8.0Hz,2H),6.96–6.87(m,2H),6.12–6.03(m,1H),4.76(dd,J＝32.0,13.6Hz,1H),4.00(d,J＝2.0Hz,3H),3.86–3.76(m,1H),3.76–3.67(m,1H),3.67–3.56(m,1H),3.39–3.29(m, 1H),3.28–2.94(m,2H),2.36(d,J＝3.6Hz,3H),2.28(t,J＝16.8Hz,1H),2.13(dd,J＝23.2,13.6Hz,1H),1.99–1.52(m,2H).13C NMR(150MHz,DMSO-d6)δ175.14,162.31,161.92(d,J＝7.5Hz),160.27(d,J＝7.7Hz),152.83,152.53,144.78,144.69,140.76,131.80(t,J＝10.6Hz),130.08,130.04,128.12,126.26,120.38,116.03(t,J＝16.6Hz),112.69,112.54,72.46,62.74,45.70,41.55,40.19,39.78,33.03,32.11,21.34.HRMS(MALDI)计算值C27H27F2N4O3S[M+H]+525.1766,实测值525.1775.
式(Ⅰ-22).白色固体；m.p.＝123-125℃.1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.67(s,1H),7.34–7.28(m,1H),6.96–6.88(m,2H),6.08(dd,J＝12.0,9.2Hz,1H),4.67(d,J＝14.4Hz,1H),4.35(d,J＝14.0Hz,1H),3.98(s,2H),3.94(s,1H),3.81(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.42–3.33(m,1H),3.33–3.19(m,1H),2.98–2.89(m,1H),2.23(d,J＝13.6Hz,2H),1.92–1.77(m,2H).13C NMR(100MHz,CDCl3)δ174.35,162.62(d,J＝7.6Hz),160.94,160.12(d,J＝7.5Hz),152.23,145.19,142.36,130.60(t,J＝10.6Hz),117.81,115.75(t,J＝16.1Hz),112.00-111.76(m),72.89,62.76,46.13,41.98,41.55,40.39,32.83,31.90.HRMS(MALDI)计算值C20H21F2N4O3S[M+H]+:435.1297,实测值435.1301.
式(Ⅰ-23).白色固体；m.p.＝142-144℃.1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.38–7.31(m,1H),6.96(t,J＝8.0Hz,2H),6.12(dd,J＝12.0,9.2Hz,1H),4.69(d,J＝13.2Hz,1H),4.24(d,J＝13.6Hz,1H),3.97(s,3H),3.85(dd,J＝17.2,12.0Hz,1H),3.67(dd,J＝17.2,9.2Hz,1H),3.40(tt,J＝11.2,4.0Hz,1H),3.32–3.22(m,1H),3.01–2.91(m,1H),2.25(d,J＝13.2Hz,2H),2.08(s,3H),1.95–1.82(m,2H).13C NMR(100MHz,CDCl3)δ174.48,164.89,162.62(d,J＝8.0Hz),160.12(d,J＝7.0Hz),152.24,151.21,145.18,130.57(t,J＝10.0Hz),117.75,115.75(t,J＝16.0Hz),111.99-111.74(m),72.87(t,J＝3.0Hz),62.23,46.67,41.76,41.54(t,J＝2.0Hz),40.54,32.84,31.88,12.96.HRMS(MALDI)计算值C21H23F2N4O3S[M+H]+449.1453,实测值449.1454.
式(Ⅰ-24).白色固体；m.p.＝58-60℃.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.40–7.30(m,1H),6.96(t,J＝8.0Hz,2H),6.11(dd,J＝12.0,9.2Hz,1H),4.71(d,J＝13.6Hz,1H),4.20(d,J＝13.6Hz,1H),3.94(s,3H),3.84(dd,J＝17.2,12.0Hz,1H),3.67(dd,J＝17.2,9.2Hz,1H),3.43–3.34(m,1H),3.32–3.22(m,1H),3.02–2.92(m,1H),2.61(q,J＝7.6Hz,2H),2.25(d,J＝13.6Hz,2H),1.95–1.79(m,2H),1.13(t,J＝7.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ175.16,163.62,162.38(d,J＝8.0Hz),159.90(d,J＝8.0Hz),156.47,152.55,144.79,131.85(t,J＝11.0Hz),120.44,116.08(t,J＝16.0Hz),112.79-112.54(m),72.50(t,J＝3.0Hz),62.18,46.31,41.61,41.13,39.86,32.98,32.18,20.25,10.06.HRMS(MALDI)计算值C22H25F2N4O3S[M+H]+463.1610,实测值463.1611.
式(Ⅰ-25).白色固体；m.p.＝72-74℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.36–7.26(m,1H),7.20(s,1H),7.13(d,J＝8.0Hz,1H),7.08(dd,J＝8.0,1.6Hz,1H),6.91(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.73(s,1H),4.01(s,3H),3.78(dt,J＝16.8,10.4Hz,2H),3.62(dd,J＝17.2,9.2Hz,1H),3.32(t,J＝11.2Hz,1H),3.19(s,1H),2.98(s,1H),2.50(s,3H),2.30(s,3H),2.29–2.11(m,2H),1.84(s,2H).13C NMR(100MHz,CDCl3)δ162.64(d,J＝7.6Hz),160.14(d,J＝7.6Hz),153.59,152.18,145.18,135.50,134.30,131.82,130.59(t,J＝10.6Hz),130.29,129.48,129.35,117.74,115.76(t,J＝16.2Hz),112.00-111.75(m),72.91(t,J＝3.0Hz).,62.71,41.56,41.54,40.52,31.93,21.75,20.94.HRMS(MALDI)计算值C28H29F2N4O3S[M+H]+539.1923,实测值539.1925.
式(Ⅰ-26).白色固体；m.p.＝70-72℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.34–7.28(m,1H),7.19(s,1H),7.13(d,J＝8.0Hz,1H),7.07(dd,J＝8.0,1.6Hz,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.74(d,J＝44.0Hz,1H),4.26(q,J＝7.2Hz,2H),3.79(dd,J＝17.2,12.0Hz,2H),3.62(dd,J＝17.0,9.2Hz,1H),3.38–3.28(m,1H),3.23–2.86(m,2H),2.50(s,3H),2.30(s,3H),2.29–2.22(m,1H),2.14(s,1H),1.88–1.76(m,2H),1.34(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ162.64(d,J＝7.5Hz),160.14(d,J＝7.5Hz),153.17,152.25,145.23,135.47,134.26,131.81,130.58(t,J＝10.7Hz),130.17,129.75,129.29,117.70,115.77(t,J＝16.2Hz),112.01-111.76(m),72.90(t,J＝3.0Hz),70.45,41.55,40.66,21.87,20.96,14.85.HRMS(MALDI)计算值C29H31F2N4O3S[M+H]+553.2079,实测值553.2083.
式(Ⅰ-27).白色固体；m.p.＝69-71℃.1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.34–7.28(m,1H),7.17(s,1H),7.13(d,J＝8.0Hz,1H),7.10–7.04(m,1H),6.91(t,J＝8.4Hz,2H),6.11–6.02(m,1H),4.82(s,1H),4.53–4.42(m,1H),3.79(dd,J＝17.2,11.2Hz,2H),3.62(dd,J＝17.2,9.2Hz,1H),3.32(d,J＝12.0Hz,1H),3.20–2.84(m,2H),2.51(s,3H),2.30(s,4H),2.16(d,J＝12.8Hz,1H),1.91–1.77(m,2H),1.33(s,3H),1.31(s,3H).13C NMR(100MHz,CDCl3)δ162.64(d,J＝7.5Hz),160.14(d,J＝7.5Hz),152.27,145.22,135.43,134.24,131.80,130.59(t,J＝10.6Hz),130.03,130.00,129.25,117.68,115.77(t,J＝16.3Hz),112.00-111.75(m),76.52,72.89,41.57,40.81,22.05,21.72,20.97.HRMS(MALDI)计算值C30H33F2N4O3S[M+H]+567.2236,实测值567.2240.
式(Ⅰ-28).白色固体；m.p.＝106-108℃.1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.69(s,1H),7.35–7.28(m,1H),6.92(t,J＝8.4Hz,2H),6.08(dd,J＝12.0,9.2Hz,1H),4.84(d,J＝13.6Hz,1H),4.24(q,J＝7.2Hz,2H),3.85–3.69(m,2H),3.63(dd,J＝17.2,9.2Hz,1H),3.54(t,J＝12.0Hz,1H),3.43(d,J＝25.6Hz,2H),2.30(d,J＝13.6Hz,2H), 2.07–1.95(m,2H),1.31(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ172.95,166.82,162.61(d,J＝8.0Hz),160.11(d,J＝8.0Hz),155.60,152.18,145.40,130.62(t,J＝10.0Hz),117.95,117.92,115.72(t,J＝16.0Hz),112.01-111.76(m),72.92(t,J＝3.0Hz),70.05,60.99,56.05,45.65,41.54,39.21,32.73,31.61,14.45.HRMS(MALDI)计算值C23H22F2N4NaO3S[M+Na]+:495.1273,实测值495.1270.
式(Ⅰ-29).黄色油状物.1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.66(s,1H),7.31(dt,J＝12.8,6.0Hz,1H),6.92(t,J＝8.0Hz,2H),6.08(t,J＝10.4Hz,1H),4.68(d,J＝14.0Hz,1H),4.37(d,J＝14.0Hz,1H),4.31–4.20(m,2H),3.81(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.32(dt,J＝33.6,11.6Hz,2H),2.94(t,J＝12.4Hz,1H),2.22(d,J＝13.2Hz,2H),1.94–1.73(m,2H),1.29(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ174.32,162.61(d,J＝7.6Hz),161.18,160.11(d,J＝7.6Hz),152.24,145.21,142.10,130.57(t,J＝10.6Hz),117.75,115.76(t,J＝16.1Hz),111.99-111.74(m),72.86(t,J＝3.0Hz),70.69,46.14,41.98,41.54,40.42,32.84,31.90,14.55.HRMS(MALDI)计算值C21H23F2N4O3S[M+H]+449.1453,实测值449.1455.
式(Ⅰ-30).白色固体；m.p.＝124-126℃.1H NMR(400MHz,CDCl3)δ7.65(d,J＝3.6Hz,1H),7.36–7.26(m,1H),6.92(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),5.17(s,1H),4.39(s,2H),3.89–3.76(m,3H),3.67–3.55(m,1H),3.36–3.27(m,1H),3.00(s,2H),2.29–2.16(m,5H),1.88–1.71(m,2H),1.34(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ174.94,167.50,167.42,162.64(d,J＝7.4Hz),160.14(d,J＝7.3Hz),152.26,145.13,130.54(t,J＝10.6Hz),117.65,115.79(t,J＝16.1Hz),111.99-111.74(m),91.45,72.87,63.19,41.57,40.80,32.64,19.05,14.37.HRMS(MALDI)计算值C23H26F2N3O3S[M+H]+462.1657,实测值462.1658.
式(I-53).白色固体；m.p.＝86 88℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.36–7.24(m,2H),6.91(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,8.0Hz,1H),4.99(dd,J＝12.0,8.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.51(dd,J＝20.0,8.0Hz,1H),3.99(d,J＝12.0Hz,1H),3.83–3.73(m,2H),3.38–3.20(m,2H),2.87(ddd,J＝13.2,12.0,4.0Hz,1H),2.19(q,J＝12.0,8.4Hz,2H),2.02–1.68(m,2H),1.17(td,J＝7.2,1.6Hz,3H).13C NMR(100MHz,CDCl3)δ174.29(d,J＝11.3Hz),165.84(d,J＝20.7Hz),162.63(d,J＝7.6Hz),160.13(d,J＝7.6Hz),152.28,145.21(d,J＝2.4Hz),130.56(t,J＝10.6Hz),117.68(d,J＝8.7Hz),115.78(t,J＝16.3Hz),111.97(d,J＝5.9Hz),111.77(d,J＝5.9Hz),103.34(d,J＝38.4Hz),72.87,65.81(d,J＝12.4Hz),64.21(d,J＝41.2Hz),46.12(d,J＝32.9Hz),42.59,42.19(d,J＝38.0Hz),41.58,32.36,31.65,15.21.HRMS(MALDI)计算值C22H23BrF2N3O3S[M+H]+:526.0606，实测值526.0604.
式(I-59).白色固体；m.p.＝121 123℃.1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.21–7.16(m,2H),7.15–7.07(m,3H),7.01(s,1H),6.84(t,J＝8.4Hz,2H),5.99(dd,J＝12.0,9.2Hz,1H),3.96(m,4H),3.71(dd,J＝17.2,12Hz,1H),3.53(dd,J＝17.2,9.2Hz,1H),3.15–3.03(m,1H),2.72(t,J＝12.0Hz,2H),2.20(s,3H),1.86(s,2H),1.38(s,2H),1.23(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ174.88,170.07,162.55(d,J＝7.6Hz),160.05(d,J＝7.5Hz),153.67,152.17,144.94,136.42,133.92,130.79–130.27(m),130.06,127.32,125.60,117.54,114.22,111.88(d,J＝5.8Hz),111.68(d,J＝5.6Hz),72.76(d,J＝3.8Hz),69.83,41.47,40.44,32.01,20.14,15.32.HRMS(MALDI)计算值C29H29F2N3NaO3S[M+Na]+:560.1790，实测值560.1790.
式(I-60).白色固体；m.p.＝123 124℃.1H NMR(400MHz,CDCl3)δ7.56(d,J＝3.5Hz,1H),7.25(dd,J＝8.4,6.4Hz,1H),7.19(s,2H),7.18–7.11(m,1H),7.02(s,1H),6.98(t,J＝6.2Hz,1H),6.85(t,J＝8.0Hz,2H),6.10–5.91(m,1H),4.63(d,J＝12.4Hz,1H),3.94–3.82(m,1H),3.73(dd,J＝16.4,4.0Hz,1H),3.66(s,2H),3.54(ddd,J＝17.2,9.2,2.4Hz,1H),3.18(tdd,J＝14.8,7.2,3.6Hz,1H),3.12–3.02(m,1H),2.81–2.68(m,1H),2.26(s,3H),2.08(d,J＝14.4Hz,1H),1.96(d,J＝10.4Hz,1H),1.75–1.52(m,3H),1.50–1.38(m,1H),1.19(t,J＝7.2Hz,1H).13C NMR(100MHz,CDCl3)δ174.40,174.16,165.17,164.81,163.91(d,J＝6.2Hz),160.00,159.42,145.68,141.94,134.78,131.20,130.08,129.68,128.59,126.78,125.40,124.92(d,J＝8.3Hz),124.07,104.20,61.51,51.40,44.95,42.19–41.80(m),40.45,38.61,32.52,31.68,21.75,14.37.HRMS(MALDI)计算值C29H29F2N3NaO3S[M+Na]+:560.1790，实测值560.1792.
式(I-63).白色固体；m.p.＝120 122℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.46(d,J＝2.8Hz,1H),7.38–7.27(m,2H),7.26–7.16(m,1H),7.07(s,1H),6.94(t,J＝8.4Hz,2H),6.14–6.03(m,1H),4.24(d,J＝12.4Hz,1H),4.15-4.06(m,2H),3.81(dd,J＝21.2,8.8Hz,2H),3.63(dd,J＝17.6,9.6Hz,1H),3.23(d,J＝11.6Hz,1H),2.94(t,J＝12.8Hz,2H),1.63(q,J＝12.4Hz,2H),1.34(t,J＝7.2Hz,3H),1.26(d,J＝16.8Hz,2H).13C NMR(100MHz,CDCl3)δ174.86,168.68,162.68(d,J＝7.5Hz),160.18(d,J＝7.4Hz),154.94,152.28,145.12,135.01,132.40,131.87,130.86,130.58(t,J＝10.6Hz),128.60,117.70,112.02,111.77,111.25,72.92,70.44,41.60,40.56,32.17,15.42.HRMS(MALDI)计算值C28H26Cl2F2N3O3S[M+H]+:592.1035,实测值592.1041.
式(I-64).白色固体；m.p.＝74 75℃.1H NMR(400MHz,CDCl3)δ7.68–7.60(m,3H),7.40–7.36(m,3H),7.30(ddt,J＝8.4,6.4,2.0Hz,1H),6.91(td,J＝8.4,2.8Hz,2H),6.07(ddd,J＝12.0,9.2,5.2Hz,1H),4.78(dd,J＝50.8,13.6Hz,1H),4.33–4.22(m,2H),3.86–3.66(m,2H),3.61(dt,J＝17.2,8.4Hz,1H),3.39–3.27(m,1H),3.10(tdd,J＝14.4,11.6,2.8Hz,1H),3.30–2.90(m,1H),2.28(dd,J＝23.6,13.2Hz,1H),2.12(d,J＝10.4Hz,1H),2.01–1.78(m,2H),1.37–1.30(m,3H).13C NMR(100MHz,CDCl3)δ174.36(d,J＝41.1Hz),163.51,163.08,160.14(d,J＝7.5Hz),152.18,151.96,145.22(d,J＝2.0Hz),130.99(d,J＝7.6Hz),130.58(t,J＝10.6Hz),130.20(d,J＝1.6Hz),128.83(d,J＝2.9Hz),126.15(d,J＝2.7Hz),117.70(d,J＝6.8Hz),115.77(t,J＝16.2Hz),111.97(d,J＝5.8Hz),111.78(d,J＝5.6Hz),73.06–72.63(m),70.67,46.11,45.33,41.54,40.52(dd,J＝38.6,9.6Hz),32.97,32.50–31.83(m),14.76(d,J＝20.8Hz).HRMS(MALDI)计算值C27H26F2N4NaO3S[M+Na]+:547.1586,实测值547.1583.
式(I-78).白色固体；m.p.＝78-80℃.1H NMR(400MHz,CDCl3)δ7.71–7.55(m,1H),7.34–7.20(m,3H),7.12(t,J＝6.8Hz,2H),6.91(t,J＝8.4Hz,2H),6.06(q,J＝10.4Hz,1H),4.97(dd,J＝8.0,1.2Hz,1H),4.65(dd,J＝36.0,13.6Hz,1H),4.12–3.93(m,2H),3.88–3.70(m,2H),3.62(dd,J＝19.6,9.2Hz,1H),3.21(d,J＝11.2Hz,1H),3.15(s,3H),2.76(t,J＝12.4Hz,1H),2.43–2.27(m,3H),2.09(t,J＝20.0Hz,2H),1.95–1.70(m,2H),0.91(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ174.84,169.95–169.10(m),162.63(d,J＝7.4Hz),160.13(d,J＝7.7Hz),152.22,145.02(d,J＝14.6Hz),137.01,132.23,130.54(t,J＝10.6Hz),129.79(d,J＝6.1Hz),129.49–129.21(m),128.76(d,J＝6.9Hz),128.62(d,J＝7.2Hz),117.64(d,J＝8.3Hz),115.86(d,J＝16.2Hz),111.96(d,J＝5.8Hz),111.77(d,J＝5.7Hz),72.86,64.66(d,J＝8.4Hz),56.16(d,J＝10.1Hz),45.43(d,J＝8.2Hz),41.62(d,J＝14.2Hz),40.47,32.19(t,J＝39.6Hz),21.12,15.07.HRMS(MALDI)计算值C30H31F2N3NaO3S[M+Na]+:574.1946，实测值574.1947.
式(I-81).白色固体；m.p.＝82-84℃.1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.48(td,J＝7.2,1.6Hz,1H),7.34–7.27(m,1H),7.25–7.21(m,1H),7.17–7.10(m,1H),7.05(ddd,J＝10.4,8.0,1.2Hz,1H),6.95–6.87(m,3H),6.06(dd,J＝12.0,9.2Hz,1H),4.21(s,1H),4.12(qd,J＝7.2,1.6Hz,1H),4.04(q,J＝7.2Hz,2H),3.78(dd,J＝17.2,12.0Hz,1H),3.60(dd,J＝17.2,9.2Hz,1H),3.26–3.12(m,1H),2.89(t,J＝12.4Hz,2H),2.00(s,2H),1.57(s,2H),1.31(td,J＝6.8,2.8Hz,3H).13C NMR(100MHz,CDCl3)δ174.98,169.39,161.38(dd,J＝251.5,7.6Hz),160.49,158.02,153.00,152.26,145.04,131.10(d,J＝3.6Hz),130.56(t,J＝10.6Hz),128.95(d,J＝8.3Hz),124.01(d,J＝3.3Hz),122.28(d,J＝14.4Hz),117.70,115.98–115.36(m),111.99,111.74,108.77,72.86,70.10,41.54,40.57,32.11,15.36.HRMS(MALDI)计算值C28H26F3N3NaO3S[M+Na]+:564.1539，实测值564.1534.
式(Ⅰ-134).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),7.00(s,1H),6.96–6.89(m,2H),6.61(dd,J＝16.8,10.6Hz,1H),6.28(dd,J＝16.8,1.6Hz,1H),6.13(dd,J＝12.0,9.2Hz,1H),5.69(dd,J＝10.6,2.0Hz,1H),4.81–4.69(m,1H),4.15–4.04(m,1H),3.87(dd,J＝17.6,12.0Hz,1H),3.68(dd,J＝17.4,9.2Hz,1H),3.28–3.13(m,1H),3.07(tt,J＝11.6,3.6Hz,1H),2.86–2.73(m,1H),2.12(d,J＝13.2Hz,2H),1.75–1.64(m,2H).HRMS(MALDI)计算值C20H20F2N3O2S[M+H]+:404.1239，实测值404.1242.
式(Ⅰ-135).白色固体；m.p.＝81-83℃.1H NMR(400MHz,CDCl3)δ7.58(d,J＝11.6Hz,1H),7.35–7.27(m,1H),7.01–6.98(m,1H),6.96–6.89(m,2H),6.12(dd,J＝12.0,9.2Hz,1H),5.70(d,J＝11.6Hz,1H),4.72(d,J＝13.6Hz,1H),3.97–3.82(m,3H),3.72–3.64(m,2H),3.26–3.12(m,1H),3.07–3.01(m,1H),2.83–2.69(m,1H),2.12–2.07(m,2H),1.72–1.65(m,2H),1.33(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ166.21,162.54(d,J＝7.6Hz),161.80,161.20,160.04(d,J＝7.5Hz),156.72,153.31,130.75(t,J＝10.6Hz),115.34(t,J＝16.0Hz),114.32,111.96(d,J＝5.9Hz),111.77(d,J＝5.2Hz),95.55,73.94,67.45,46.44–44.90(m),40.56,38.69,32.15,31.33,27.06,14.72.HRMS(MALDI)计算值C22H24F2N3O3S[M+H]+:448.1501，实测值448.1501.
式(Ⅱ-1).白色固体；m.p.＝96-98℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.35–7.27(m,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.84(t,J＝5.6Hz,1H),4.69(d,J＝13.6Hz,1H),4.02(d,J＝13.6Hz,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.42(d,J＝2.4Hz,6H),3.35–3.27(m,1H),3.20(t,J＝12.8Hz,1H),2.79(t,J＝12.8Hz,1H),2.71(t,J＝5.2Hz,2H),2.18(t,J＝13.6Hz,2H),1.87–1.68(m,2H).13C NMR(100MHz,CDCl3)δ174.62,167.84,162.62(d,J＝7.6Hz),160.12(d,J＝7.5Hz),152.26,145.18,130.55(t,J＝10.7Hz),117.66,115.77(t,J＝16.1Hz),111.98-111.73(m),103.33,72.85(t,J＝3.0Hz),54.82,54.58,45.76,41.56(d,J＝2.4Hz),41.44,40.50,37.75,32.80,32.09.HRMS(MALDI)计算值C22H25F2N3NaO4S[M+Na]+488.1426,实测值488.1426.
式(Ⅱ-2).黄色油状物.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.38–7.30(m,1H),6.95(t,J＝8.0Hz,2H),6.10(dd,J＝12.0,9.2Hz,1H),4.98(t,J＝5.6Hz,1H),4.73(d,J＝13.6Hz,1H),4.11(d,J＝12.0Hz,1H),3.89–3.72(m,3H),3.70–3.57(m,3H),3.39–3.29(m,1H),3.23(t,J＝12.8Hz,1H),2.86–2.69(m,3H),2.20(s,2H),1.93–1.71 (m,2H),1.25(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ174.67,168.07,162.62(d,J＝7.6Hz),160.12(d,J＝7.7Hz),152.29,145.16,130.55(t,J＝10.6Hz),117.60,115.78(t,J＝16.1Hz),111.98-111.73(m),101.72,72.85(t,J＝3.0Hz),63.35,63.15,45.96,41.57,41.45,40.57,38.76,32.81,32.20,15.40,15.38.HRMS(MALDI)计算值C24H29F2N3NaO4S[M+Na]+516.1739,实测值516.1738.
式(Ⅱ-3).黄色油状物.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.35–7.26(m,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.93–4.87(m,1H),4.73–4.63(m,1H),4.09–4.01(m,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.76–3.68(m,1H),3.67–3.54(m,2H),3.42(d,J＝3.2Hz,3H),3.35–3.26(m,1H),3.25–3.16(m,1H),2.85–2.76(m,1H),2.76–2.66(m,2H),2.23–2.13(m,2H),1.86–1.67(m,2H),1.22(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ174.66,168.06,162.63(d,J＝7.6Hz),160.13(d,J＝7.6Hz),152.27,145.16,130.54(t,J＝10.6Hz),117.63,115.77(t,J＝16.2Hz),111.98-111.73(m),102.54,72.86(t,J＝3.0Hz),63.45,54.52,45.90,41.56,41.49,40.52,38.16,32.80,32.10,15.35(d,J＝2.9Hz).HRMS(MALDI)计算值C23H28F2N3O4S[M+H]+:480.1763,实测值480.1761.
式(Ⅱ-4).黄色油状物.1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.39–7.31(m,1H),6.95(t,J＝8.0Hz,2H),6.11(dd,J＝12.0,9.2Hz,1H),4.98(q,J＝4.8Hz,1H),4.77–4.69(m,1H),4.15–4.08(m,1H),3.90–3.73(m,2H),3.70–3.58(m,3H),3.54–3.46(m,1H),3.39–3.29(m,1H),3.23(t,J＝12.8Hz,1H),2.86–2.70(m,3H),2.20(s,2H),1.84(s,2H),1.64(q,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,3H),0.99–0.92(m,3H).13C NMR(100MHz,CDCl3)δ174.66,168.08,162.60(d,J＝7.7Hz),160.10(d,J＝7.5Hz),152.27,145.14,130.54(t,J＝10.6Hz),117.62,115.76(t,J＝16.2Hz),111.96-111.71(m),101.80(d,J＝7.1Hz),72.82(t,J＝2.9Hz),69.43(d,J＝16.3Hz),63.15(d,J＝20.2Hz),45.95(d,J＝6.2Hz),41.55,41.42(d,J＝4.0Hz),40.55(d,J＝3.1Hz),38.65,32.80,32.17,23.09,15.37(d,J＝2.9Hz),10.63(d,J＝2.2Hz).HRMS(MALDI)计算值C25H31F2N3NaO4S[M+Na]+530.1896,实测值530.1899.
式(Ⅱ-5).黄色油状物.1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.38(t,J＝4.8Hz,4H),7.35–7.32(m,2H),6.96(t,J＝8.0Hz,2H),6.11(dd,J＝12.0,9.2Hz,1H),5.15(t,J＝5.6Hz,1H),4.81–4.70(m,2H),4.64(dd,J＝11.6,4.8Hz,1H),4.08(d,J＝13.6Hz,1H),3.90–3.75(m,2H),3.71–3.60(m,2H),3.31(d,J＝4.4Hz,1H),3.19(q,J＝12.0Hz,1H),2.92–2.73(m,3H),2.19(d,J＝13.6Hz,2H),1.89–1.68(m,2H),1.27(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ174.64,167.91,162.64(d,J＝7.6Hz),160.14(d,J＝7.6Hz),152.30,145.18,137.99,130.55(t,J＝10.6Hz),128.40,127.83,127.75,127.69,117.60,115.80(t,J＝16.2Hz),111.99-111.74(m),101.52,72.86(t,J＝3.2Hz),69.35,63.09,45.92,41.58,40.52,38.70,32.69,32.00,15.40,15.38.HRMS(MALDI)计算值C29H31F2N3NaO4S[M+Na]+530.1896,实测值530.1897.
式(Ⅱ-6).白色固体；m.p.＝58-60℃.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.34–7.27(m,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.74(d,J＝13.6Hz,1H),4.51(dd,J＝15.2,8.0Hz,1H),4.10(dd,J＝25.2,13.6Hz,1H),3.81(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.42(d,J＝6.8Hz,6H),3.32(s,1H),3.19(dd,J＝22.8,11.4Hz,1H),3.05(q,J＝7.2Hz,1H),2.89–2.69(m,1H),2.21(dd,J＝27.9,12.8Hz,2H),1.92–1.65(m,2H),1.16(dd,J＝7.2,3.2Hz,3H).13C NMR(100MHz,CDCl3)δ175.00,172.25,162.64(d,J＝7.8Hz),160.14(d,J＝7.5Hz),152.27,145.15,130.55(t,J＝10.6Hz),117.63,115.79(t,J＝16.1Hz),111.99-111.74(m),107.72,72.88,56.80,53.75,45.82,41.84,41.59,40.78,39.44,32.95,32.38,13.81.HRMS(MALDI)计算值C23H27F2N3NaO4S[M+Na]+502.1583,实测值502.1583.
式(Ⅱ-7).黄色油状物.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.38–7.24(m,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.74(dd,J＝32.8,13.6Hz,1H),4.48(dd,J＝8.0,5.6Hz,1H),4.23–4.10(m,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.45–3.34(m,6H),3.34–3.26(m,1H),3.26–3.15(m,1H),3.02–2.93(m,1H),2.92–2.73(m,1H),2.29–2.12(m,2H),1.91–1.59(m,4H),0.92–0.81(m,3H).13C NMR(100MHz,CDCl3)δ175.09,171.50,162.63(d,J＝7.5Hz),160.13(d,J＝7.6Hz),152.29,145.17,130.55(t,J＝10.6Hz),117.61,115.77(t,J＝16.1Hz),111.98-111.73(m),107.37,72.86(t,J＝3.0Hz).,56.82,53.99,46.89,41.95,41.56,40.83,40.51,32.99,32.47,22.10,11.63.HRMS(MALDI)计算值C23H27F2N3NaO4S[M+Na]+516.1739,实测值516.1742.
式(Ⅱ-8).黄色油状物.1H NMR(400MHz,CDCl3)δ7.66(d,J＝3.6Hz,1H),7.34–7.26(m,1H),6.92(t,J＝8.0Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),4.82–4.63(m,1H),4.46(dd,J＝8.4,2.0Hz,1H),4.16(dd,J＝18.8,14.4Hz,1H),3.80(dd,J＝16.8,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.41(d,J＝2.8Hz,3H),3.37(s,1H),3.34–3.25(m,1H),3.25–3.15(m,1H),3.09–3.00(m,1H),2.93–2.70(m,1H),2.28–2.13(m,2H),1.94(s,2H),1.80–1.69(m,2H),1.58–1.47(m,1H),1.43–1.33(m,1H),1.33–1.17(m,2H),0.98–0.88(m,3H).13C NMR(100MHz,CDCl3)δ175.10,171.63,162.63(d,J＝7.5Hz),160.13(d,J＝7.7Hz),152.29,145.17,130.54(t,J＝10.6Hz),117.68,115.78(t,J＝16.2Hz),111.98-111.73(m),107.51,77.39,77.07,76.75,72.86,56.86,53.97,46.03,45.19,41.96,41.55,40.84,33.18,31.07,22.61,20.42,14.16.HRMS(MALDI)计算值C25H31F2N3NaO4S[M+Na]+530.1896,实测值530.1899.
式(Ⅱ-9).黄色油状物.1H NMR(400MHz,CDCl3)δ7.66(d,J＝4.0Hz,1H),7.34–7.27(m,1H),6.92(t,J＝8.0Hz, 2H),6.07(dd,J＝12.0,9.2Hz,1H),4.73(dd,J＝42.0,13.2Hz,1H),4.46(dd,J＝8.0,3.6Hz,1H),4.16(t,J＝16.7Hz,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.47(s,1H),3.44–3.39(m,3H),3.37(s,1H),3.35–3.27(m,1H),3.26–3.15(m,1H),3.06–2.99(m,1H),2.93–2.72(m,1H),2.18(t,J＝15.6Hz,2H),1.98–1.86(m,1H),1.83–1.68(m,2H),1.62–1.52(m,1H),1.40–1.11(m,5H),0.88(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ174.72,171.65,162.63(d,J＝7.5Hz),160.14(d,J＝7.7Hz),152.28,145.16,130.54(t,J＝10.6Hz),117.67,115.78(t,J＝16.3Hz),111.98-111.73(m),107.52,72.87,56.87,53.95,46.03,45.36,41.98,41.56,40.85,33.01,32.50,29.41,28.71,22.83,13.99.HRMS(MALDI)计算值C26H33F2N3NaO4S[M+Na]+544.2052,实测值544.2055.
式(Ⅱ-10).白色固体；m.p.＝69-71℃.1H NMR(400MHz,CDCl3)δ7.68–7.56(m,1H),7.38(d,J＝5.6Hz,2H),7.36–7.26(m,4H),6.91(t,J＝8.4Hz,2H),6.05(q,J＝11.2Hz,1H),4.98(d,J＝8.0Hz,1H),4.65(dd,J＝40.0,13.6Hz,1H),4.11–3.96(m,2H),3.85–3.68(m,1H),3.67–3.55(m,1H),3.54–3.48(m,3H),3.25–3.16(m,2H),3.14(d,J＝2.4Hz,3H),2.77(s,1H),2.16–2.04(m,1H),1.87(d,J＝12.8Hz,1H),1.82–0.77(m,2H).13C NMR(100MHz,CDCl3)δ174.72,169.09,162.63(d,J＝7.4Hz),160.13(d,J＝7.4Hz),152.19,144.95,135.33,130.54(t,J＝10.7Hz),128.84,128.76,127.50,117.67,117.59,115.78(t,J＝16.0Hz),111.99-111.74(m),107.42,107.30,72.86,56.56,55.50,53.15,45.43,41.76,41.55,40.44,32.22,31.77.HRMS(MALDI)计算值C28H29F2N3NaO4S[M+Na]+564.1739,实测值564.1738.
式(Ⅱ-11).白色固体；m.p.＝126-128℃.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.38–7.31(m,1H),6.95(t,J＝8.4Hz,2H),6.11(dd,J＝12.0,9.2Hz,1H),4.77(d,J＝13.2Hz,1H),4.14(dd,J＝14.4,7.4Hz,1H),4.05–3.94(m,4H),3.84(dd,J＝17.2,12.0Hz,1H),3.66(dd,J＝17.2,9.2Hz,1H),3.39–3.29(m,1H),3.24(t,J＝12.8Hz,1H),2.89–2.75(m,3H),2.22(s,2H),1.81(dd,J＝28.8,13.6Hz,2H),1.52(s,3H).13C NMR(100MHz,CDCl3)δ174.79,167.48,162.61(d,J＝7.5Hz),160.11(d,J＝7.5Hz),152.26,145.15,130.56(t,J＝10.7Hz),117.69,115.76(t,J＝16.2Hz),111.98-111.73(m),108.71,72.85(t,J＝3.0Hz),64.78,64.74,46.49,43.10,41.55,41.41,40.51,32.82,32.15,24.66.HRMS(MALDI)计算值C23H25F2N3NaO4S[M+Na]+500.1426,实测值500.1425.
式(Ⅱ-12).黄色油状物.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.37–7.31(m,1H),6.95(t,J＝8.0Hz,2H),6.10(dd,J＝12.0,9.2Hz,1H),4.76(d,J＝12.8Hz,1H),4.32–4.18(m,1H),4.14–4.06(m,2H),3.84(dd,J＝17.2,12.0Hz,1H),3.66(dd,J＝17.2,9.2Hz,1H),3.54–3.40(m,1H),3.38–3.29(m,1H),3.24(s,1H),2.86(s,1H),2.85–2.76(m,2H),2.21(s,2H),1.81(dd,J＝32.4,12.7Hz,2H),1.52(d,J＝21.2Hz,3H),1.32(d,J＝6.0Hz,3H).13C NMR(100MHz,CDCl3)δ174.79,167.64,162.61(d,J＝7.6Hz),160.11(d,J＝7.5Hz),152.27,145.14,130.56(t,J＝10.6Hz),117.68,115.76(t,J＝16.1Hz),111.97-111.72(m),108.95,72.84,70.98,46.49,44.05,43.30,41.54,41.39,40.49,32.77,32.16,24.83,18.26.HRMS(MALDI)计算值C24H27F2N3NaO4S[M+Na]+514.1583,实测值514.1580.
式(II-18).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.31(tt,J＝8.4,6.6Hz,1H),6.92(t,J＝8.3Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),5.07(q,J＝5.6Hz,1H),4.72–4.61(m,1H),4.04–3.90(m,3H),3.80(dd,J＝17.1,12.0Hz,1H),3.63(dd,J＝17.1,9.2Hz,1H),3.44(d,J＝2.8Hz,3H),3.31(tt,J＝11.4,3.9Hz,1H),3.21(t,J＝11.9Hz,1H),2.86–2.68(m,3H),2.24–2.12(m,2H),1.87–1.66(m,2H).13C NMR(100MHz,CDCl3)δ174.53,167.10(d,J＝2.5Hz),162.67(d,J＝7.6Hz),160.17(d,J＝7.5Hz),152.31,145.23(d,J＝3.6Hz),130.61(t,J＝10.6Hz),122.47(q,J＝278.2Hz),117.77(d,J＝3.5Hz),115.80(t,J＝16.3Hz),112.00(d,J＝5.8Hz),111.81(d,J＝5.9Hz),102.94(d,J＝7.3Hz),72.90,64.75–63.33(m),54.71(d,J＝20.6Hz),45.71(d,J＝3.0Hz),41.57,41.49(d,J＝3.8Hz),40.47(d,J＝8.5Hz),37.69(d,J＝20.2Hz),32.73,32.05.HRMS(MALDI)计算值C23H24F5N3NaO4S[M+Na]+:556.1300，实测值556.1301.
式(II-19).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.42–7.19(m,1H),6.92(t,J＝8.2Hz,2H),6.07(dd,J＝11.9,9.1Hz,1H),5.12(q,J＝5.2Hz,1H),4.68(d,J＝13.3Hz,1H),4.05–3.90(m,3H),3.86–3.69(m,2H),3.69–3.55(m,2H),3.31(tt,J＝11.4,3.9Hz,1H),3.21(t,J＝12.6Hz,1H),2.86–2.67(m,3H),2.19(t,J＝13.7Hz,2H),1.88–1.64(m,2H),1.27–1.20(m,3H).13C NMR(100MHz,CDCl3)δ174.53,171.20,167.21,162.66(d,J＝7.6Hz),160.16(d,J＝7.7Hz),152.31,145.22(d,J＝4.2Hz),130.59(t,J＝10.6Hz),123.87(q,J＝278.1Hz),117.73(d,J＝6.2Hz),115.81(t,J＝16.2Hz),111.99(d,J＝5.7Hz),111.80(d,J＝5.6Hz),102.01(d,J＝9.7Hz),72.90,64.58–63.56(m),63.42(d,J＝17.7Hz),45.80,41.55(d,J＝7.6Hz),40.51(d,J＝6.4Hz),38.19(d,J＝6.6Hz),32.73(d,J＝6.6Hz),32.10,15.16.HRMS(MALDI)计算值C24H26F5N3NaO4S[M+Na]+:570.1456，实测值570.1455.
式(Ⅱ-21).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.36–7.30(m,1H),6.99–6.88(m,2H),6.09(dd,J＝12.0,9.2Hz,1H),5.07(t,J＝5.2Hz,1H),4.71(d,J＝13.4Hz,1H),4.15–4.09(m,2H),4.05(d,J＝13.4Hz,1H),3.89–3.78(m,3H),3.65(dd,J＝17.2,9.2Hz,1H),3.32(tt,J＝11.6,3.6Hz,1H),3.25–3.16(m,1H),2.85–2.76(m,1H),2.73(dd,J＝5.2,1.6Hz,2H),2.25–2.09(m,3H),1.88–1.70(m,2H),1.43–1.33(m,1H).13C NMR(100MHz,CDCl3)δ174.65,167.33,162.55(d,J＝7.6Hz),160.05(d,J＝7.6Hz),152.21,145.07,130.47(t,J＝10.6Hz),117.60,115.70(t,J＝16.2Hz),111.88(d,J＝5.8Hz),111.69(d,J＝5.8Hz),99.82,72.79(t,J＝2.9Hz),66.93(d,J＝1.9Hz),45.74,41.48(t,J＝2.1Hz),41.39,40.45,39.20,32.71,31.96,25.50.HRMS(MALDI)计算值C23H25F2N3NaO4S[M+Na]+:500.1426，实测值500.1424.
式(Ⅱ-22).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.36–7.25(m,1H),6.91(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),5.31(t,J＝4.8Hz,1H),4.71(d,J＝13.6Hz,1H),4.03–3.88(m,5H),3.79(dd,J＝ 17.1,12.0Hz,1H),3.62(dd,J＝16.8,9.2Hz,1H),3.34–3.24(m,1H),3.24–3.16(m,1H),2.85–2.74(m,3H),2.18(t,J＝16.2Hz,2H),1.87–1.70(m,2H).13C NMR(100MHz,CDCl3)δ174.57,167.24,162.60–162.51(m),160.17–160.00(m),152.21,145.11,130.50,117.65,115.71,111.91,111.71,101.82,72.82,64.94,45.63,41.50,41.30,40.45,38.29,32.71,31.93.HRMS(MALDI)计算值C22H23F2N3NaO4S[M+Na]+:486.1270，实测值486.1268.
式(Ⅱ-23).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.35–7.26(m,1H),6.91(t,J＝8.0Hz,2H),6.06(t,J＝10.4Hz,1H),4.68(s,1H),4.26(t,J＝6.4Hz,1H),4.07–3.96(m,1H),3.91–3.68(m,3H),3.62(dd,J＝17.2,9.2Hz,1H),3.30(t,J＝11.6Hz,1H),3.19(s,1H),2.83-2.72(m,1H),2.55-2.44(m,1H),2.24–2.02(m,4H),1.90(t,J＝7.2Hz,2H),1.84–1.69(m,2H),1.64–1.51(m,1H).HRMS(MALDI)计算值C23H25F2N3NaO3S[M+Na]+:484.1477，实测值484.1476.
式(Ⅱ-24).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.33–7.27(m,1H),6.95–6.87(m,2H),6.06(dd,J＝12.0,9.2Hz,1H),4.66(d,J＝13.2Hz,1H),4.02–3.90(m,2H),3.91–3.80(m,1H),3.80–3.71(m,2H),3.62(dd,J＝17.2,9.2Hz,1H),3.43(t,J＝6.8Hz,1H),3.29(tt,J＝11.2,4.0Hz,1H),3.18(t,J＝12.8Hz,1H),2.79(m,1H),2.71(m,1H),2.52–2.39(m,2H),2.25–2.11(m,3H),1.82–1.69(m,2H),1.56(m,1H).13C NMR(100MHz,CDCl3)δ174.45,170.00,162.56(d,J＝7.7Hz),160.06(d,J＝7.5Hz),152.16,145.12,130.50(t,J＝10.6Hz),117.64,115.69(t,J＝16.2Hz),111.89(d,J＝5.9Hz),111.70(d,J＝5.7Hz),73.27,72.80(t,J＝3.1Hz),67.58,45.14,41.49,41.32,40.45,37.02,35.49,32.72,32.18,32.05.HRMS(MALDI)计算值C23H25F2N3NaO3S[M+Na]+:484.1477，实测值484.1475.
式(Ⅱ-25).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.33–7.26(m,1H),6.94–6.87(m,2H),6.06(dd,J＝11.6,9.2Hz,1H),4.69(t,J＝14.8Hz,1H),4.08–3.99(m,1H),3.96–3.91(m,1H),3.84–3.74(m,2H),3.61(dd,J＝17.2,9.2Hz,1H),3.51–3.40(m,1H),3.34–3.21(m,1H),3.23–3.11(m,1H),2.84–2.71(m,1H),2.73–2.61(m,1H),2.39–2.28(m,1H),2.21–2.10(m,2H),1.85–1.67(m,4H),1.59–1.45(m,3H),1.37–1.26(m,1H).13C NMR(100MHz,CDCl3)δ174.88,174.67,169.46,169.30,162.58(d,J＝7.5Hz),160.08(d,J＝7.6Hz),152.21,145.07(d,J＝5.0Hz),130.48(t,J＝10.7Hz),117.60,115.72(t,J＝16.1Hz),111.90(d,J＝6.0Hz),111.71(d,J＝5.6Hz),75.12(d,J＝12.7Hz),72.81(t,J＝2.9Hz),68.54,45.74(d,J＝7.4Hz),41.50,40.53(d,J＝8.0Hz),40.19(d,J＝13.7Hz),32.82,32.03(d,J＝9.9Hz),25.78,23.35.HRMS(MALDI)计算值C24H27F2N3NaO3S[M+Na]+:498.1633，实测值498.1634.
式(Ⅱ-26).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.39–7.30(m,1H),6.94(t,J＝8.5Hz,2H),6.14–6.05(m,1H),4.71(d,J＝13.0Hz,1H),3.99(d,J＝11.2Hz,1H),3.94–3.78(m,3H),3.65(dd,J＝12.8,9.6Hz,1H),3.53–3.41(m,1H),3.40–3.27(m,1H),3.23(t,J＝10.0Hz,2H),2.81(t,J＝12.4Hz,1H),2.33(dd,J＝14.8,6.8 Hz,1H),2.29–2.13(m,3H),2.01(s,1H),1.98–1.90(m,1H),1.85–1.70(m,2H),1.69–1.61(m,2H),1.39–1.28(m,1H).HRMS(MALDI)计算值C24H27F2N3NaO3S[M+Na]+:498.1633，实测值498.1631.
式(Ⅱ-27).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.33–7.26(m,1H),6.96–6.80(m,2H),6.05(dd,J＝12.0,9.2Hz,1H),4.67(d,J＝13.4Hz,1H),4.02–3.90(m,3H),3.78(dd,J＝16.8,12.0Hz,1H),3.61(dd,J＝17.2,9.2Hz,1H),3.46–3.37(m,2H),3.29(tt,J＝11.6,4.0Hz,1H),3.18(t,J＝12.8Hz,1H),2.77(t,J＝12.4Hz,1H),2.27(d,J＝7.2Hz,2H),2.24–2.12(m,2H),2.11–2.03(m,1H),1.81–1.70(m,2H),1.70–1.64(m,2H),1.38-1.26(m,2H).13C NMR(100MHz,CDCl3)δ174.49,169.93,162.54(d,J＝7.5Hz),160.04(d,J＝7.6Hz),152.12,145.10,130.49(t,J＝10.6Hz),117.65,115.66(t,J＝16.2Hz),111.88(d,J＝5.9Hz),111.69(d,J＝5.7Hz),72.81(t,J＝3.1Hz),67.80,45.38,41.46,41.31,40.45,39.91,33.06,32.82,32.60,32.08.HRMS(MALDI)计算值C24H27F2N3NaO3S[M+Na]+:498.1633，实测值498.1627.
式(Ⅱ-28).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.66–7.63(m,1H),7.33–7.26(m,1H),6.94–6.86(m,2H),6.09–6.02(m,1H),5.18–5.13(m,1H),4.68(d,J＝13.4Hz,1H),4.01(d,J＝13.6Hz,1H),3.94–3.86(m,2H),3.84–3.74(m,1H),3.72–3.63(m,2H),3.63–3.57(m,1H),3.34–3.24(m,1H),3.18(t,J＝12.8Hz,1H),2.77(t,J＝12.8Hz,1H),2.72–2.66(m,2H),2.14(t,J＝14.8Hz,2H),1.80–1.70(m,6H).HRMS(MALDI)计算值C24H27F2N3NaO4S[M+Na]+:514.1583，实测值514.1581.
式(Ⅱ-31).白色固体；m.p.＝75 77℃.1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.50–7.41(m,1H),7.34–7.26(m,1H),7.20–7.12(m,3H),6.91(t,J＝8.4Hz,2H),6.11–6.00(m,1H),4.91(d,J＝7.6Hz,1H),4.76–4.53(m,1H),4.28–4.17(m,1H),3.91–3.68(m,2H),3.67–3.56(m,1H),3.54(s,3H),3.27–3.13(m,1H),3.09(s,3H),2.95–2.83(m,1H),2.82–2.69(m,1H),2.43(s,3H),2.15–1.95(m,2H),1.57–1.45(m,1H),0.73–0.58(m,1H).HRMS(MALDI)计算值C29H31F2N3NaO4S[M+Na]+:578.1896，实测值578.1894.
式(Ⅱ-32).白色固体；m.p.＝89 91℃.1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.34–7.27(m,1H),7.23–7.14(m,3H),7.07(t,J＝6.8Hz,1H),6.91(td,J＝8.0,3.2Hz,2H),6.05(dd,J＝11.2Hz,J＝20.8Hz,1H),4.98(d,J＝8.0Hz,1H),4.72–4.57(m,1H),4.03–3.96(m,1H),3.80–3.72(m,1H),3.66–3.56(m,1H),3.51(s,3H),3.26–3.18(m,1H),3.15(s,3H),2.99(t,J＝11.6Hz,1H),2.81–2.72(m,1H),2.33(s,3H),2.16–2.06(m,1H),1.93–1.80(m,1H),1.81–1.73(m,1H),1.58–1.48(m,1H),0.93–0.81(m,1H).HRMS(MALDI)计算值C29H31F2N3NaO4S[M+Na]+:578.1896,实测值578.1895.
式(Ⅱ-33).浅黄色固体；m.p.＝90 92℃.1H NMR(400MHz,CDCl3)δ7.67–7.56(m,1H),7.33–7.26(m,3H),7.13(d,J＝7.6Hz,2H),6.91(t,J＝8.0Hz,2H),6.05(dd,J＝20.4Hz,J＝10.0Hz,1H),4.96(dd,J＝8.0,2.0Hz,1H),4.73–4.55(m,1H),4.05–3.96(m,1H),3.85–3.69(m,1H),3.66–3.54(m,1H),3.51(d,J＝2.0Hz,3H),3.27–3.17(m,1H),3.15(s,3H),2.97(t,J＝12.4Hz,1H),2.76(t,J＝12.4Hz,1H),2.35–2.27(m,3H),2.16–2.02(m,2H),1.91–1.78(m,1H),1.59–1.46(m,1H),0.96–0.81(m,1H).HRMS(MALDI)计算值C29H31F2N3NaO4S[M+Na]+:578.1896,实测值578.1897.
式(Ⅱ-34).白色固体；m.p.＝93 95℃.1H NMR(400MHz,CDCl3)δ7.66–7.56(m,1H),7.34–7.26(m,2H),7.06(d,J＝7.6Hz,1H),6.99–6.86(m,3H),6.10–6.01(m,1H),4.90(d,J＝8.0Hz,1H),4.76–4.56(m,1H),4.22–4.09(m,1H),3.90–3.60(m,3H),3.54(d,J＝6.4Hz,3H),3.26–3.14(m,1H),3.10(d,J＝4.8Hz,3H),2.93–2.68(m,1H),2.38(d,J＝3.2Hz,3H),2.28(d,J＝4.0Hz,3H),2.16–2.05(m,1H),1.92–1.72(m,2H),1.56–1.44(m,1H),0.68–0.56(m,1H).HRMS(MALDI)计算值C30H33F2N3NaO4S[M+Na]+:592.2052，实测值592.2044.
式(Ⅱ-35).白色固体；m.p.＝90 92℃.1H NMR(400MHz,CDCl3)δ7.66–7.56(m,1H),7.37–7.28(m,2H),7.00–6.95(m,2H),6.94–6.87(m,2H),6.10–6.00(m,1H),4.92–4.86(m,1H),4.74–4.54(m,1H),4.23–4.13(m,1H),3.91–3.68(m,2H),3.67–3.56(m,1H),3.53(d,J＝2.8Hz,3H),3.23–3.12(m,1H),3.10(s,3H),2.94–2.68(m,1H),2.39(d,J＝2.8Hz,3H),2.30–2.24(m,3H),2.19–1.96(m,2H),1.91–1.72(m,1H),1.57–1.44(m,1H),0.75–0.63(m,1H).HRMS(MALDI)计算值C30H33F2N3NaO4S[M+Na]+:592.2052，实测值592.2044.
式(Ⅱ-37).白色固体；m.p.＝98 100℃.1H NMR(400MHz,CDCl3)δ7.67–7.56(m,1H),7.53–7.46(m,1H),7.34–7.27(m,1H),7.25–7.20(m,1H),6.98–6.87(m,4H),6.10–6.00(m,1H),5.13–5.04(m,1H),4.72–4.52(m,2H),4.21(t,J＝15.6Hz,1H),3.86(s,3H),3.82–3.70(m,1H),3.67–3.53(m,1H),3.50(s,3H),3.28–3.19(m,1H),3.15(s,3H),3.02–2.93(m,1H),2.80–2.68(m,1H),2.15–2.07(m,1H),1.91–1.72(m,1H),1.52–1.40(m,1H),0.88–0.76(m,1H).HRMS(MALDI)计算值C29H31F2N3NaO5S[M+Na]+:594.1845，实测值594.1843.
式(Ⅱ-39).白色固体；m.p.＝113 115℃.1H NMR(400MHz,CDCl3)δ7.71–7.62(m,2H),7.33–7.28(m,2H), 7.21–7.16(m,1H),6.95–6.87(m,2H),6.12–6.02(m,1H),5.00(dd,J＝8.0,2.8Hz,1H),4.72–4.58(m,2H),4.27–4.10(m,1H),3.88–3.55(m,2H),3.51(d,J＝4.0Hz,3H),3.39–3.24(m,1H),3.21(s,3H),3.16–3.08(m,1H),2.88–2.75(m,1H),2.20–2.09(m,2H),1.97–1.72(m,1H),1.64–1.05(m,1H).HRMS(MALDI)计算值C28H27Cl2F2N3NaO4S[M+Na]+:632.0960，实测值632.0963.
式(Ⅱ-70).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),6.98(s,1H),6.92(t,J＝8.4Hz,2H),6.12(t,J＝10.8Hz,1H),4.97–4.92(m,1H),4.72(d,J＝13.6Hz,1H),4.06(d,J＝13.6Hz,1H),3.90–3.80(m,1H),3.77–3.65(m,3H),3.61–3.53(m,2H),3.15(t,J＝12.8Hz,1H),3.02(t,J＝12.4Hz,1H),2.79–2.65(m,3H),2.12–2.02(m,2H),1.77–1.58(m,2H),1.26–1.16(m,6H).13C NMR(100MHz,CDCl3)δ167.97,162.51(d,J＝7.6Hz),161.10,160.00(d,J＝7.6Hz),156.72,153.29,130.74(t,J＝10.6Hz),115.30(t,J＝16.2Hz),114.27,111.94(d,J＝5.9Hz),111.74(d,J＝5.5Hz),101.67,73.89(t,J＝3.0Hz),63.17(d,J＝17.2Hz),46.24,41.76,40.50(d,J＝2.3Hz),38.71,38.50,32.14(d,J＝4.1Hz),31.30(d,J＝4.7Hz),15.31(d,J＝2.6Hz).HRMS(MALDI)计算值C24H30F2N3O4S[M+H]+:494.1920，实测值494.1923.
式(Ⅱ-71).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),6.98(s,1H),6.92(t,J＝8.4Hz,2H),6.12(t,J＝10.8Hz,1H),4.90(s,1H),4.72(d,J＝13.2Hz,1H),4.03(d,J＝13.6Hz,1H),3.90–3.81(m,1H),3.76–3.55(m,3H),3.41(s,3H),3.16(t,J＝12.8Hz,1H),3.01(t,J＝12.0Hz,1H),2.71(s,3H),2.14–2.02(m,2H),1.76–1.58(m,2H),1.26–1.18(m,3H).13C NMR(100MHz,CDCl3)δ167.85,162.52(d,J＝7.5Hz),161.08,160.02(d,J＝7.4Hz),156.74,153.30,130.75(t,J＝10.6Hz),115.32(t,J＝16.2Hz),114.30,111.95(d,J＝5.8Hz),111.76(d,J＝5.7Hz),102.49,73.90(d,J＝2.9Hz),63.28(d,J＝15.2Hz),54.59(d,J＝24.3Hz),46.15(d,J＝2.2Hz),41.77(d,J＝1.9Hz),40.53,38.49(d,J＝2.9Hz),38.22(d,J＝17.6Hz),32.18(d,J＝3.8Hz),31.34–31.19(m),15.30(d,J＝3.1Hz).HRMS(MALDI)计算值C23H28F2N3O4S[M+H]+:480.1763，实测值480.1760.
式(Ⅱ-79).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),7.00(s,1H),6.96–6.89(m,2H),6.13(dd,J＝12.0,9.2Hz,1H),4.77(d,J＝11.6Hz,1H),4.11–4.04(m,1H),3.99–3.84(m,5H),3.69(dd,J＝17.6,9.2Hz,1H),3.23–3.12(m,1H),3.05(tt,J＝12.0,3.6Hz,1H),2.81(s,2H),2.76–2.67(m,1H),2.14–2.06(m,2H),1.74–1.61(m,2H),1.48(s,3H).13C NMR(100MHz,CDCl3)δ167.42,162.51(d,J＝7.6Hz),161.15,160.01(d,J＝7.4Hz),156.71,153.29,130.75(t,J＝10.7Hz),115.30(t,J＝16.2Hz),114.47–114.15(m),111.95(d,J＝5.8Hz),111.75(d,J＝5.9Hz),108.70,73.91(t,J＝3.1Hz),64.69(d,J＝4.7Hz),46.87–46.49(m),43.00,41.97–41.70(m),40.52(d,J＝2.5Hz),38.52–38.26(m),32.30–31.91(m),31.40–31.02(m),30.17,24.64.HRMS(MALDI)计算值C23H26F2N3O4S[M+H]+:478.1607，实测值478.1611.
式(Ⅱ-81).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),6.99(s,1H),6.96–6.89(m,2H),6.13(dd,J＝12.0,9.2Hz,1H),4.87(d,J＝7.2Hz,1H),4.73(d,J＝13.6Hz,1H),3.98(d,J＝13.2Hz,1H),3.87(dd,J＝17.2,12.0Hz,1H),3.68(dd,J＝17.2,9.2Hz,1H),3.42(s,3H),3.18(t,J＝12.8Hz,1H),3.09–2.97(m,2H),2.80–2.70(m,2H),2.17–2.05(m,5H),1.74–1.61(m,2H).HRMS(MALDI)计算值C22H26F2N3O3S2[M+H]+:482.1378，实测值482.1380.
式(Ⅱ-82).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),7.00(s,1H),6.96–6.89(m,2H),6.13(dd,J＝12.0,9.2Hz,1H),4.95–4.90(m,1H),4.73(d,J＝13.2Hz,1H),3.98(d,J＝13.2Hz,1H),3.89(dd,J＝17.2,12.0Hz,1H),3.69(dd,J＝17.2,9.2Hz,1H),3.42(s,3H),3.18(t,J＝12.8Hz,1H),3.10–2.99(m,2H),2.82–2.72(m,2H),2.68–2.61(m,2H),2.16–2.05(m,2H),1.74–1.61(m,2H),1.28(t,J＝7.6Hz,3H).HRMS(MALDI)计算值C23H28F2N3O3S2[M+H]+:496.1535，实测值496.1530.
式(Ⅱ-85).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.27(m,1H),6.99(s,1H),6.96–6.89(m,2H),6.13(dd,J＝12.0,9.2Hz,1H),4.97–4.92(m,1H),4.78–4.68(m,1H),4.05–3.96(m,1H),3.91–3.78(m,2H),3.68(dd,J＝17.2,9.2Hz,1H),3.51–3.45(m,1H),3.18(t,J＝12.8Hz,1H),3.09–2.99(m,2H),2.81–2.69(m,2H),2.13–2.06(m,5H),1.75–1.62(m,2H),1.20(t,J＝7.2Hz,3H).HRMS(MALDI)计算值C23H28F2N3O3S2[M+H]+:496.1535，实测值496.1536.
式(Ⅱ-87).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.27(m,1H),6.99(s,1H),6.96–6.89(m,2H),6.12(dd,J＝12.0,9.2Hz,1H),5.14–5.09(m,1H),4.71(d,J＝13.4Hz,1H),4.03–3.82(m,4H),3.78–3.57(m,3H),3.18(t,J＝12.8Hz,1H),3.09–3.00(m,1H),2.78–2.68(m,3H),2.14–2.05(m,2H),1.74–1.62(m,2H),1.24–1.19(m,3H).HRMS(MALDI)计算值C24H27F5N3O4S[M+H]+:548.1637，实测值548.1642.
式(Ⅱ-92).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),7.00(s,1H),6.96–6.89(m,2H),6.13(dd,J＝12.4,9.2Hz,1H),4.72(d,J＝13.4Hz,1H),4.01–3.92(m,2H),3.91–3.83(m,2H),3.79–3.74(m,1H),3.73 –3.64(m,1H),3.48–3.42(m,1H),3.22–3.12(m,1H),3.08–2.98(m,1H),2.76–2.67(m,2H),2.53–2.40(m,2H),2.21–2.06(m,3H),1.71–1.61(m,2H),1.60–1.52(m,1H).13C NMR(100MHz,CDCl3)δ169.98,162.53(d,J＝7.3Hz),160.97,160.03(d,J＝7.6Hz),156.80,153.28,130.76(t,J＝10.7Hz),115.24(d,J＝16.4Hz),114.38,111.96(d,J＝5.7Hz),111.77(d,J＝5.5Hz),73.93,73.31,67.61,45.56,41.72,40.56,38.52,37.05,35.56,32.28,32.21,31.25.HRMS(MALDI)计算值C29H31F2N3NaO5S[M+H]+:594.1845，实测值594.1843.
式(Ⅱ-93).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.37–7.29(m,1H),6.99(s,1H),6.97–6.89(m,2H),6.17–6.08(m,1H),4.78–4.69(m,1H),4.04(d,J＝13.6Hz,1H),3.98–3.89(m,1H),3.88–3.76(m,2H),3.68(dd,J＝17.4,9.2Hz,1H),3.50–3.42(m,1H),3.21–3.09(m,1H),3.08–2.98(m,1H),2.79–2.63(m,2H),2.39–2.31(m,1H),2.14–2.03(m,2H),1.86–1.60(m,4H),1.58–1.46(m,3H),1.37–1.27(m,1H).13C NMR(100MHz,CDCl3)δ169.22(d,J＝8.4Hz),162.51(d,J＝7.5Hz),161.16(d,J＝8.8Hz),160.01(d,J＝7.5Hz),156.69(d,J＝3.0Hz),153.29,130.73(t,J＝10.6Hz),115.31(t,J＝16.2Hz),114.29(d,J＝5.0Hz),111.94(d,J＝5.8Hz),111.74(d,J＝5.9Hz),75.06(d,J＝5.9Hz),73.90(t,J＝3.0Hz),68.52(d,J＝1.8Hz),46.04(d,J＝2.3Hz),41.78(d,J＝2.0Hz),40.53,40.16(d,J＝13.0Hz),38.52,32.37–32.20(m),32.00(d,J＝8.4Hz),31.24(t,J＝5.2Hz),25.79,23.33(d,J＝2.2Hz).HRMS(MALDI)计算值C24H27F2N3NaO3S[M+Na]+:498.1633，实测值498.1637.
式(Ⅱ-95).浅黄色油状物.1H NMR(400MHz,CDCl3)δ7.36–7.27(m,1H),7.00(s,1H),6.96–6.89(m,2H),6.12(dd,J＝12.0,9.2Hz,1H),4.73(d,J＝12.8Hz,1H),4.01–3.89(m,3H),3.88–3.82(m,1H),3.68(dd,J＝17.4,9.2Hz,1H),3.42(td,J＝11.8,2.0Hz,2H),3.22–3.11(m,1H),3.04(tt,J＝11.6,3.6Hz,1H),2.71(t,J＝10.6Hz,1H),2.28(d,J＝6.8Hz,2H),2.17–2.05(m,3H),1.72–1.61(m,4H),1.39–1.27(m,2H).HRMS(MALDI)计算值C24H28F2N3O3S[M+H]+:476.1814，实测值476.1818.
式(Ⅱ-103).白色固体；m.p.＝95 97℃.1H NMR(400MHz,CDCl3)δ7.38–7.27(m,2H),7.00–6.89(m,5H),6.16–6.06(m,1H),4.89(dd,J＝7.6,3.2Hz,1H),4.77–4.63(m,1H),4.19(dd,J＝17.2,8.0Hz,1H),3.89–3.57(m,3H),3.53(d,J＝3.2Hz,3H),3.09(d,J＝2.0Hz,3H),3.00–2.80(m,1H),2.68(t,J＝13.2Hz,1H),2.39(d,J＝2.6Hz,3H),2.29–2.20(m,3H),1.98(d,J＝13.6Hz,1H),1.81–1.65(m,2H),1.46–1.35(m,1H),0.70–0.59(m,1H).HRMS(MALDI)计算值C30H34F2N3O4S[M+H]+:570.2233，实测值570.2238.
式(Ⅱ-105).白色固体；m.p.＝97 99℃.1H NMR(400MHz,CDCl3)δ7.54–7.47(m,1H),7.36–7.28(m,1H),7.24 –7.17(m,1H),6.99–6.86(m,4H),6.74(s,1H),6.16–6.07(m,1H),5.12–5.06(m,1H),4.74–4.59(m,2H),4.22(t,J＝15.6Hz,1H),3.86(s,3H),3.82–3.76(m,1H),3.70–3.59(m,1H),3.49(d,J＝1.8Hz,3H),3.15(s,3H),3.13–3.07(m,1H),3.02–2.86(m,1H),2.71–2.63(m,1H),2.02–1.93(m,1H),1.84–1.75(m,1H),1.42–1.30(m,1H),0.79–0.65(m,1H).HRMS(MALDI)计算值C29H32F2N3O5S[M+H]+:572.2025，实测值572.2029.
测试例1：抑制黄瓜霜霉病的活体活性
测试和调查方法参照康卓、顾宝根编写的《农药生物活性测试标准操作规范》杀菌剂卷中的SOP-SC-1098黄瓜霜霉病盆栽法。测试结果见表1、表2、表3，表中的“/”项表示未测试(下文中的情况均相同)。其中，对照药剂氟噻唑吡乙酮(OXA)的结构式如下：
对活性测试结果中各防治效果等级的说明：90％≤A≤100％；75％≤B＜90％；60％≤C＜75％；45％≤D＜60％；0％≤E＜45％。
目标化合物对黄瓜霜霉病室内活体杀菌活性筛选结果。
表1：目标化合物对黄瓜霜霉病室内杀菌活体活性

为进一步探索化合物结构与活性之间的关系，本发明对黄瓜霜霉病室内活体杀菌活性测试初筛的最低浓度(1.25mg/L)下防效超过75％的部分化合物进行了降低浓度的杀菌活性复筛实验。实验结果如表2中所示。
表2：目标化合物对黄瓜霜霉病室内杀菌活体活性复筛
由上述活性结果可知，本发明的多个化合物对黄瓜霜霉病具有良好的防治效果，在20mg/L至1.25mg/L的三个施药浓度下，有多个化合物防效在75％至100％，与对照药剂氟噻唑吡乙酮相当，在活性复筛环节中，本发明的4个化合物(Ⅱ-3、Ⅱ-4、Ⅱ-18、Ⅱ-19)杀菌活性优异，在0.078mg/L施药浓度下，具有90％及以上的防效，与相同浓度下的氟噻唑吡乙酮药效相当，优于烯酰吗啉和氰霜唑的防效，最重要的是，本发明的化合物II-3和Ⅱ-18在0.005mg/L施药浓度下的防效与对照药剂OXA相当，具有进一步开发的价值。
与现有最接近化合物的比对：表3中的对比化合物(对比1-对比7)活性数据来源：Li,J.L.et al.Pestic.Biochem. Phys.2020,169,104673.DOI:doi.org/10.1016/j.pestbp.2020.104673。通过表3中的对比可以看出，本发明中多数化合物在0.625mg/L浓度下对黄瓜霜霉病的防效要高于对比化合物。
表3：对比化合物对黄瓜霜霉病室内杀菌活体活性结果
注：防效等级：90％≤A≤100％；75％≤B＜90％；60％≤C＜75％；45％≤D＜60％；0％≤E＜45％
测试例2：抑制卵菌病原菌菌丝生长的离体活性
采用微孔板法进行药剂室内生物活性的测定。辣椒疫霉、大豆疫霉、致病疫霉、烟草疫霉菌的培养：将靶标菌接种在PDB或V8汁液体培养基内摇培72-96h，过滤后收集新鲜的菌丝，然后称取0.1g菌丝体，放入50ml的PDB液体培养基后，用组织捣碎机把菌丝体捣碎成小菌丝段，制成菌丝段悬浮液，置于4℃下备用。
致病疫霉菌的培养：将致病疫霉接种于V8培养基平板后培养12d，待其产生大量孢子囊后，加入无菌水并将平板转移到4℃冰箱内放置1h，然后再转移到室温内，诱导游动孢子释放。待游动孢子充分释放后，配置孢子浓度为105个/mL的孢子悬浮液，置于4℃下备用。
将供试药剂用DMSO配制成2000mg/L的母液，然后用无菌水稀释成系列梯度浓度药液，置于4℃下备用。
把孢子悬浮液(菌丝段悬浮液)和提前配制的系列梯度药液按100μl+100μl的量依次加入到每个微孔内，然后将96孔微孔板置于25℃(致病疫霉18℃)的培养箱内静置培养，3-4d(致病疫霉7d)后用酶标仪检测各处理的OD595值。计算药剂对靶标菌的室内毒力。结果列于表4中。
抑制率％＝(空白处理OD595-药剂处理OD595)/(空白处理OD595-参比OD595)*100
表4：目标化合物Ⅱ-3、Ⅱ-18对卵菌病原菌菌丝生长的抑制活性
注：抑制活性等级：90％≤A≤100％；75％≤B＜90％；60％≤C＜75％；
从表4的结果可知，化合物Ⅱ-3和Ⅱ-18对卵菌病原菌菌丝生长有良好抑制活性，在5、0.5、0.05mg/L施药浓度下，对辣椒疫霉、大豆疫霉、致病疫霉、烟草腐霉的抑制活性均与对照药剂OXA相当。
测试例3：防治黄瓜霜霉病的田间药效试验
本试验按照《农药田间药效施药准则(一)杀菌剂防治黄瓜霜霉病》(GB/T 17980.26-2000)实施。试验地点为江苏南京湖熟蔬菜基地，以黄瓜霜霉病为靶标，以氟噻唑吡乙酮和银法利为对照药剂，试验作物为黄瓜，品种为“绿芯”。小组排列采用随机区组排列,每个小区约8m2，每处理3次重复。采用整株茎叶喷雾，试验于黄瓜霜霉病发生初期进行，连续施药2次，第1次施药后5天进行第2次施药。调查方法是在每处理小区中每排黄瓜作一个调查点，调查所有黄瓜苗所有叶片的霜霉病发生程度，并计算病情指数和防效，结果见表5中。
表5.目标化合物Ⅱ-3对黄瓜霜霉病的田间防治效果
测试结果表明，化合物Ⅱ-3防治黄瓜霜霉病效果良好，能有效保护新叶片并能有效抑制已发病叶片上的病斑蔓延。田间防治黄瓜霜霉病时剂量为50mg/L，间隔5～7天连续施药2～3次能有效控制霜霉病的发生。在50mg/L试验剂量下，防效优于对照药剂OXA和银法利。
测试例4：防治马铃薯晚疫病的田间药效试验
本试验按照《农药田间药效施药准则(一)杀菌剂防治马铃薯晚疫病》(GB/T 17980.34-2000)实施。试验地点为陕西岐山，以马铃薯晚疫病为靶标，以市售增威赢绿(10％氟噻唑吡乙酮可分散油悬浮剂)为对照药剂，试验作物为马铃薯。小组排列采用随机区组排列，每处理3次重复。采用整株茎叶喷雾，试验于马铃薯晚疫病发生 初期进行，连续施药2次，第1次施药后7天进行第2次施药。调查方法是每小区对角线五点取样，每点选二株，每株调查中上部叶片约20张。记录调查的总叶数、病叶数和病级数，并计算病情指数和防效，结果见表6中。
表6：目标化合物Ⅱ-3对马铃薯晚疫病的田间防治效果
结果表明5wt％的Ⅱ-3乳油防治马铃薯晚疫病效果良好，能有效保护新叶片并能有效抑制已发病叶片上的病斑蔓延。田间防治马铃薯晚疫病时剂量为30～40毫升/亩，间隔5～7天连续施药2～3次能有效控制马铃薯晚疫病的发生，防效优于剂量为15～20毫升/亩下的市售增威赢绿的防效。即相同的有效成分用量下，5wt％的Ⅱ-3乳油的防效优于增威赢绿。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。

Claims (10)

  1. 一种含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，该化合物具有式(I)所示的结构，
    其中，在式(I)中，X1和X2中的一者为S，另一者为CH；R为式(Q1)所示的结构或式(Q2)所示的结构；
    在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子的3-7元饱和杂环基；A为N或CH；且当A为N时，R2和R3中的一者不存在；
    在式(Q2)中，R1、R2、R3、R4各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基，且R1、R2、R3、R4中的至少一者为C1-C12的烷氧基或C1-C12的烷硫基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
    所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成。
  2. 根据权利要求1所述的化合物，其中，在式(I)中，
    X1和X2中的一者为S，另一者为CH；
    R为式(Q1)所示的结构；在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
    A为N或CH；且当A为N时，R2和R3中的一者不存在；
    所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成；
    优选地，在式(I)中，
    X1和X2中的一者为S，另一者为CH；
    R为式(Q1)所示的结构；在式(Q1)中，R1、R2、R3各自独立地选自H、C1-C10的烷基、C1-C10的烷氧基、C3-C10的环烷基、C1-C10的烷硫基、由至少一个卤素取代的C1-C10的烷氧基、由苯基取代的C1-C10的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
    A为N或CH；且当A为N时，R2和R3中的一者不存在；
    所述组合A由C1-C10的烷基、卤素、由至少一个卤素取代的C1-C10的烷基、C1-C10的烷氧基组成。
  3. 根据权利要求2所述的化合物，其中，式(I)所示结构的化合物选自以下中的任意一种：













  4. 根据权利要求1所述的化合物，其中，在式(I)中，
    X1和X2中的一者为S，另一者为CH；
    R为式(Q2)所示的结构；R1、R2、R3、R4各自独立地选自H、C1-C12的烷基、C1-C12的烷氧基、C3-C12的环烷基、C1-C12的烷硫基、由至少一个卤素取代的C1-C12的烷氧基、由苯基取代的C1-C12的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；且R1、R2、R3、R4中的至少一者为C1-C12的烷氧基或C1-C12的烷硫基，或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
    所述组合A由C1-C12的烷基、卤素、由至少一个卤素取代的C1-C12的烷基、C1-C12的烷氧基组成；
    优选地，在式(I)中，
    X1和X2中的一者为S，另一者为CH；
    R为式(Q2)所示的结构；R1、R2、R3、R4各自独立地选自H、C1-C10的烷基、C1-C10的烷氧基、C3-C10的环烷基、C1-C10的烷硫基、由至少一个卤素取代的C1-C10的烷氧基、由苯基取代的C1-C10的烷氧基、卤素、苯基、由组合A中的至少一种基团取代的苯基、氰基、硝基、吡啶基、吡唑基、由组合A中的至少一种基团取代的吡唑基；且R1、R2、R3、R4中的至少一者为C1-C10的烷氧基或C1-C10的烷硫基，或者，R2和R3一起环合形成未取代或由组合A中的至少一种基团取代的含有至少一个O原子作为成环原子的3-7元饱和杂环基；
    所述组合A由C1-C10的烷基、卤素、由至少一个卤素取代的C1-C10的烷基、C1-C10的烷氧基组成。
  5. 根据权利要求4所述的化合物，其中，式(I)所示结构的化合物选自以下中的任意一种：







  6. 一种制备权利要求1-5中任意一项所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物的方法，其特征在于，该方法包括：在缩合反应条件下，将式(II)所示的化合物与式(III)所示的化合物进行接触反应，
    且式(II)所示的化合物与式(III)所示的化合物中的取代基的定义与权利要求1-5中任意一项所述的定义相同。
  7. 权利要求1-5中任意一项所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物在防治植物卵菌病害中的应用；
    优选地，所述植物卵菌病害选自黄瓜霜霉病、马铃薯晚疫病、辣椒疫霉病中的至少一种。
  8. 权利要求1-5中任意一项所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物作为农用杀菌剂的应用。
  9. 一种杀菌剂，该杀菌剂由活性成分和辅料组成，所述活性成分包括权利要求1-5中任意一项所述的含链状羧酸酰胺结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物；
    优选地，所述活性成分的含量为1-99.9重量％。
  10. 根据权利要求9所述的杀菌剂，其中，该杀菌剂的剂型选自乳油、悬浮剂、可湿性粉剂、粉剂、粒剂、水剂、毒饵、母液和母粉中的至少一种。
PCT/CN2023/115117 2022-08-26 2023-08-26 含链状羧酸酰胺结构的化合物及其制备方法和应用、杀菌剂 Ceased WO2024041654A1 (zh)

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